Good morning, and welcome to the IDEAYA Biosciences Investor Webcast. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the IDEAYA Biosciences website following the conclusion of the event. I'd now like to turn the call over to your host, Yujiro Hata, Founder and Chief Executive Officer of IDEAYA Biosciences. Please go ahead, Yujiro. This is Yujiro Hata, Founder and CEO of IDEAYA Biosciences, and I'll be the host today for the darovasertib clinical program update in neoadjuvant uveal melanoma. Please note, we will be making forward-looking statements today, and please refer to our SEC filings as appropriate. I wanted to first begin by welcoming all of our listeners, analysts, and guest speakers to today's event. Our speakers today will be Dr. Carol Shields, the Chief of Ocular Oncology at the Wills Eye Hospital at Thomas Jefferson University, and Dr. Darrin Beaupre, the Chief Medical Officer of IDEAYA Biosciences. For today's agenda, I'll provide a brief market introduction of pre-metastatic uveal melanoma, then Dr. Darrin Beaupre will provide a walkthrough of the registrational trial design feedback in neoadjuvant uveal melanoma from the recent FDA Type C meeting. Next, Dr. Carol Shields will provide a comprehensive phase 2 clinical data update of darovasertib in the neoadjuvant uveal melanoma setting, including a summary of patient baseline characteristics, safety, and clinical efficacy. I will then provide closing remarks, and then we will finish with the analyst Q&A portion of the webcast. The pre-metastatic uveal melanoma market can be summarized by three key points. First, this is an indication that is an extraordinarily high unmet medical need, with currently no FDA-approved systemic therapies in either the neoadjuvant or adjuvant settings. Second, we believe the pre-metastatic uveal melanoma market is substantially higher than the metastatic uveal melanoma, with an annual incidence of approximately 12,000 patients across North America, Europe, and Australia. Finally, third, we believe the total addressable uveal melanoma prevalence is multiples of annual incidence, partly driven by approximately 30% of small ocular tumors that are currently managed with wait and see, as they have no existing treatment options. We believe darovasertib treatment has the potential to be applicable to all uveal melanoma patients in the neoadjuvant setting. I'll now introduce Dr. Darrin Beaupre, who will walk through the regulatory feedback on the darovasertib neoadjuvant uveal melanoma registrational trial design from our recent FDA Type C meeting. Darrin, please take it away. Thank you, Yujiro. On this slide, we display the potential for darovasertib to impact the entire patient journey of subjects with both localized and disseminated uveal melanoma. We have clinical trials either open or planned that address all facets of the disease. Beginning in the metastatic setting, we are currently executing a randomized phase 2/3 trial in HLA-A2 negative uveal melanoma patients, comparing the darovasertib and crizotinib combination versus standard of care, such as immunotherapy. Key endpoints for this trial include progression-free survival and overall survival. In addition, in HLA-A2 positive subjects, we're continuing to evaluate the efficacy of this combination in our ongoing phase 2 trial, IDE 196-001. With respect to subjects with primary uveal melanoma, we are evaluating the activity of darovasertib as a single agent in the neoadjuvant setting in study IDE196-009, with tumor reduction, enucleation prevention, vision preservation, and radiation reduction as key endpoints. Further information about longer-term plans in this setting will be addressed in the next two slides. Due to the fact that darovasertib inhibits a key driver pathway in this disease, we also believe we have the opportunity to prevent metastases by treating subjects in the adjuvant setting. Therefore, in summary, darovasertib in early clinical testing has been found to have a significant impact in uveal melanoma patients, and we are constructing a development plan that will address all aspects of this disease. Next slide, please. Transitioning to the darovasertib neoadjuvant uveal melanoma registrational trial design update, the following are highlights based on regulatory guidance from the recent FDA Type C meeting. First, eye preservation rate and time to vision loss are acceptable primary endpoints for enucleation and plaque brachytherapy uveal melanoma patients treated in a randomized phase 3 setting. Importantly, the FDA briefing book outlined an objective to exceed a lower bound of 10% eye preservation rate with a 95% confidence interval. Next, no detriment to event-free survival was an acceptable secondary endpoint. Discussions are ongoing with the FDA to include overall response as a potential surrogate and composite endpoint to support earlier approval scenarios. In fact, at the meeting, a preliminary primary uveal melanoma response criteria was proposed. The response criteria was supported by preliminary correlations between degree of response with eye sparing and visual preservation. These aspects were discussed. Further validation of response criteria and imaging modalities utilized to assess response will be provided to the FDA as requested. The registrational study will enroll high-risk metastatic disease uveal melanoma patients. Based on our preliminary projections, we anticipate that no detriment to event-free survival results for this high-risk population will take approximately two years of data maturity to initial readout. Also, based on the FDA meeting, the potential for a broad indication label in neoadjuvant uveal melanoma for subjects with low, intermediate, and high risk for metastatic disease is feasible. A darovasertib dose of 30 milligrams twice a day was proposed as the move forward dose for the registration trial. Next slide, please. This slide summarizes from a high level the proposed phase 3 design for the darovasertib neoadjuvant study. Eligible subjects will be uveal melanoma patients with localized disease that are at high risk for metastases. There will be two cohorts of patients. Cohort one will include subjects who require enucleation based on large tumor size. The second cohort of subjects will be those who have tumors that are deemed eligible for plaque brachytherapy. In both cohorts, subjects will be randomized to either immediate local therapy versus six to twelve months of neoadjuvant, neoadjuvant darovasertib treatment, followed by definitive local therapy. The primary endpoint for cohort one will be eye preservation, and that for cohort two will be time to vision loss. Key secondary endpoints will include event-free survival and safety. Additional endpoints to be discussed with the FDA include overall response rate, time to macular edema, and predicted visual outcomes. Based on this high-level plan, we believe the study will include approximately four hundred patients, with the potential for an early data evaluation at approximately two years. This concludes the regulatory update for the darovasertib neoadjuvant program, and I'll pass it back to you, Yujiro. Thank you, Darrin, for that terrific walkthrough, and thanks to the entire clinical and regulatory team for the tremendous effort that enabled successful Type C meeting with the FDA. With that, I'll now introduce our guest speaker, Dr. Carol Shields, a leading global key opinion leader in ocular oncology and the Chief of Ocular Oncology at the Wills Eye Hospital, who will walk us through the darovasertib neoadjuvant uveal melanoma phase 2 clinical data update. Dr. Shields, please take it away. Thank you, Yujiro. Primary uveal melanoma represents 5% of all diagnosed melanomas. Most, of course, occur in the skin. It's molecularly driven by GNAQ and GNA11 mutations. This tumor most often arises in the choroid, a layer of the back of the eye, and the treatment depends on several factors, in particular, tumor size, the height and width. Enucleation and plaque radiotherapy are the primary uveal melanoma treatments. There is no FDA-approved systemic therapy for primary uveal melanoma, and this highlights the high unmet medical need. Next slide. One method of management of this tumor is enucleation when a patient has a large tumor, and in this, these four diagrams illustrations, you can see we are removing an eye that will leave the patient with an artificial eye and no hope for vision from that artificial eye. Next slide. Another alternative for treatment is plaque brachytherapy. This is a meaningful treatment for uveal melanoma. On the bottom, you can see the radioactive plaque, which is sewn to the back of the eye, provides radiation to the melanoma inside the eye, and it is effective for treating this tumor. But it leaves the patient with complications, such as radiation-related swelling of the optic nerve and swelling of the retina, which means vision loss. So many of these patients, or I should say most of them, wind up blind from the radiation. Next slide. On this slide, we depict the biology behind the pathogenesis of uveal melanoma and the signaling pathway responsible for the growth and the survival of uveal melanoma cells. The vast majority of patients diagnosed with uveal melanoma have an activating mutation in GNAQ or GNA11... in their tumor cells. These alterations are responsible for activating the PKC, or protein kinase C, downstream, and this is a key driver for this disease. Ultimately, this results in stimulation of downstream pathways such as RAS, RAF, MEK, and ERK, all of which promote growth and survival of uveal melanoma cells. darovasertib is an orally available, potent and selective inhibitor of protein kinase C. In preclinical models, it demonstrated anti-tumor activity at drug exposures that could be safely achieved in humans. Therefore, the premise for the clinical testing of darovasertib in the neoadjuvant setting was to reduce tumor size, which could spare the need for enucleation, and to treat with radiation reduction and ultimate reduction of metastatic disease and preservation of vision. Next slide. The global company-sponsored clinical trial design to test this hypothesis is shown in this slide. Two distinct uveal melanoma patient populations are eligible for this study. The first, labeled as Cohort 1, are subjects who have large, localized tumors that would have required enucleation or eye removal. In the second cohort, are patients with small to mid-size tumors that are planned for treatment with plaque brachytherapy. So in both arms, patients are eligible to receive darovasertib 300 milligrams BID as neoadjuvant therapy to maximum benefit, or for up to 12 months of total therapy. Once definitive localized treatment is provided, patients are then eligible to receive darovasertib for 12 months in the adjuvant setting for reduction of metastatic disease. The primary endpoints for this study include safety for both cohorts and, in addition, enucleation sparing for Cohort 1 and radiation reduction for Cohort 2. Additional endpoints include evaluation of tumor response, vision outcomes, and local and distant relapse. Next slide, please. This slide provides the demographics of patient, the patient population that has thus far been evaluated in the company-sponsored trial. As of the cutoff date of August 15th, 2024, there were 19 patients enrolled in the enucleation cohort and 19 patients in the plaque brachytherapy cohort, for a total of 38 patients. Approximately 60% of patients were less than 65 years of age, and 40% over age 65. For those patients in the enucleation group, the median tumor thickness was 10 millimeters, and median largest basal diameter, 17 millimeters. These are large tumors, and that's consistent with an eye that requires enucleation. The median distance to critical visual structures, such as the fovea and optic disc, was only 2 millimeters. For the plaque brachytherapy cohort, the tumors were a little bit smaller, with a median thickness of 6 millimeters and a median base of 13 millimeters. These tumors were slightly further from the visual structures. Next slide, please. Here we list the cumulative safety profile from the 38 patients treated with neoadjuvant darovasertib therapy in the company-sponsored trial. You will see that the most common drug-related adverse events were diarrhea, nausea, vomiting, and fatigue, but they were all Grade 1 or 2, with the majority of adverse events being very low grade. Grade 3 or higher adverse events were uncommon, as were serious adverse events. There was a low frequency of discontinuation of medication due to treatment-related adverse events. It was under 3%, and overall, darovasertib was well-tolerated in this treatment setting. Next slide, please. In this waterfall plot, we show combined data from both the company-sponsored trial, as well as that from the investigator-sponsored trial recently presented at the American Society of Clinical Oncology in 2024. The investigator-sponsored trial evaluated darovasertib in the neoadjuvant setting for subjects planned for enucleation. The combined data shown here provides a comprehensive overview of the degree of tumor shrinkage seen when darovasertib is used as a neoadjuvant medication. There was a total of forty-nine subjects used for this analysis. As you can see from the waterfall plot, the majority of subjects treated with this medication experienced tumor shrinkage below the zero mark. 59% had at least 20% tumor reduction, and nearly 50% observed greater than or equal to 30% tumor reduction based on product of diameter measurements. Importantly, 61% of patients were spared enucleation, and that is a highly significant clinical outcome. We have never had a medication that can do this. In addition, tumor reduction of 20% or greater was found to correlate with enucleation sparing and radiation reduction in this population. 43% of patients were continuing on darovasertib neoadjuvant therapy at the time of the analysis. Next slide, please, so this is a swim lane plot of the same 49 patients. We reviewed the treatment duration of subjects eligible for six months or more of darovasertib neoadjuvant therapy treated in the investigator-sponsored trial and the company-sponsored trial. As you can see from this plot, the majority of subjects received greater than three cycles of treatment, and several had sustained tumor shrinkage beyond six months of therapy. Subjects with large and small to mid-sized tumors responded similarly, and determination of the risk profiles of these subjects and its impact on response is currently being evaluated. 61% or 19 of 31 eye preservation rate observed in the enucleation patients, and the typical time to greater than or equal to 30% tumor shrinkage was about two months, and the typical time for conversion from enucleation to saving the eye and treating with plaque brachytherapy was about 5.5 months. Next slide, please. In the next few slides, I will show you some really interesting images demonstrating case examples of the impact of darovasertib when given in the neoadjuvant setting from the company-sponsored trial. In this first case, we have a man, very young, in his twenties, with a very large intraocular melanoma that's impinging on the critical visual structures, such as the macula and the optic disc. This patient has a mutation in the GNA11 gene. This patient was enrolled in the enucleation cohort, headed for enucleation or removal of the eye, but was subsequently converted to plaque brachytherapy due to substantial reduction in tumor size, seen in the photos and the ultrasounds. After five months of treatment, the patient had 39% reduction in tumor thickness, 47% reduction in the product of diameter measurements, and 54% decrease in tumor volume. Next slide, please. In this second case example, was a man in his sixties who was enrolled in the plaque brachytherapy cohort due to tumor size. After five months of darovasertib treatment, the patient had 60% reduction in tumor thickness, 71% reduction in product of diameter measurements, and 80% decrease in tumor volume. Reduction is... In the simulated radiation dose to the critical eye structures is listed at month three, with patient continuing in neoadjuvant therapy past six months, allowing him to have further potential tumor size reduction prior to plaque brachytherapy. These two examples that I've just shown you show the impact that darovasertib has on preserving the eye in the first case and preserving the vision in the second case. Next slide, please. Neoadjuvant therapy with darovasertib can also have significant impact on patients with small to mid-sized tumors. In this population, due to a decrease in tumor size, a reduced dose of radiation can be used, which can subsequently lead to reduced radiation toxicity and improved visual outcomes. A few case examples are shown here. In the top graphic, we see a subject with uveal melanoma outlined in red, who required plaque brachytherapy but was first treated with six months of darovasertib neoadjuvant therapy. This subject experienced tumor reduction of 64% based on product of diameter measurements, and that's the smaller red circle, top graphic. In the bottom panel, comparing the simulated radiation dose required for plaque brachytherapy at the time of enrollment to the simulated dose after darovasertib treatment, neoadjuvant therapy was associated with a radiation dose reduction of 63% to the fovea, which is the center of vision, and 63% to the optic nerve and 63% to the optic disc, both of which are the transmitters of vision. For the second subject, who has thus far received only three cycles of neoadjuvant therapy. Tumor reduction of 30% was observed, which resulted in 40%-50% reduction in radiation dose that was initially planned to key visual structures. On the left panel, there are currently a total of 10 patients who are evaluable for pre- and post-simulation data analysis. The mean reduction of radiation to key visual structures is shown in the left for the fovea, the optic nerve, and the optic disc, all very important in vision. Importantly, 60% of these subjects had improved predictive visual outcome using a visual prognostication tool that can predict the likelihood of developing vision loss to 20/200 or worse. That is an outcome consistent with legal blindness. Therefore, in summary, neoadjuvant therapy with darovasertib was found to be an effective means to reduce tumor size in subjects with primary uveal melanoma. Further tumor reduction was associated with enucleation sparing, that is, no need to remove the eye anymore, and radiation reduction, that is, less radiation to the eye with improved predicted visual outcomes. I would like to take a breather and just give my personal opinion of this medication. This data that you have just seen is a true game changer for the management of uveal melanoma. I've practiced ocular oncology for four decades, and this is the first agent that can be used in the neoadjuvant setting to shrink an intraocular melanoma before definitive therapy. This is the first drug to be used as neoadjuvant and adjuvant, and this is truly remarkable. But what is more impressive is that this drug could actually be lowering the metastatic risk from uveal melanoma. I think we will soon learn of the myriad of benefits from this exceptional drug to shrink melanoma so that enucleation's not necessary, to shrink melanoma so that lower radiation dose can be given, to shrink melanoma so that less radiation-related blindness occurs, and most importantly, to shrink melanoma so that metastatic disease might reduce or even might disappear. Imagine that, and it is all based on good science. Thank you. Thank you, Dr. Shields, for that wonderful walkthrough and for all your contributions to the darovasertib program, including as a key investigator in the ongoing phase II neoadjuvant uveal melanoma clinical trial. We will now transition to our closing remarks. We believe pre-metastatic uveal melanoma is a significant indication opportunity for darovasertib. It has both an annual incidence and total prevalence that is multiples of metastatic uveal melanoma. Next, the unmet need in both the neoadjuvant and adjuvant uveal melanoma settings are significant, with currently no FDA-approved systemic therapies available for patients and a strong desire from the physician and patient communities to have better alternatives to highly invasive procedures such as eye removal and high radiation dose plaque brachytherapy. The FDA Type C meeting provides ideal important clarity on the primary endpoints of eye preservation and time to vision loss, as well as the secondary endpoint of no detriment to event-free survival for potential regulatory approval in the neoadjuvant uveal melanoma setting. We're particularly excited that the FDA agreed with the sponsor's view of the clinical importance of eye preservation and time to vision loss as primary endpoints for full approval. We believe, based on the phase II clinical data shared today, including the majority of patients observing greater than 20% ocular tumor shrinkage and eye preservation, we have a potential path for darovasertib to achieve these clinical endpoints in the neoadjuvant uveal melanoma setting. We're now seeking to rapidly advance darovasertib to a registrational trial for neoadjuvant uveal melanoma, alongside our ongoing registrational trial in frontline metastatic uveal melanoma. We believe these collective efforts advance our broader strategic objective to position darovasertib as the first-line standard of care in both the pre-metastatic and metastatic setting. We have now concluded our prepared remarks. And operator, you may now proceed to the analyst Q&A portion of our webcast. Thank you, Yujiro. Please hold for a brief moment while we pull for questions. Our first question comes from Anupam Rama at JP Morgan. Please go ahead, Anupam. Hey, guys. Thanks so much for taking the question, and congrats on the update. Just two quick ones from me. The first one, in your discussions with the FDA, what remained the kind of push-pull levers to consider here with diameter ORR as a basis for early accelerated approval in the neoadjuvant setting? And then second question, and sorry if I missed this, can you give a little bit more color on what the grade three AEs were, and if they resolved or how they were addressed? Thanks so much. Sure. Thanks, Anupam, for the question. Darrin, do you want to take that? Sure. With respect to, you know, some of the other endpoints that would be highly relevant for a study like this, like overall response, time to macular edema, radiation reduction, things that we're looking, many of the things that we're looking at already in the ongoing trial, those will still be an important component of the go-forward registration plan. But we're still working with the FDA to determine what's the best way to operationalize those endpoints to be an important component of the regulatory filing. So the good news is the FDA, you know, agreed with eye preservation and time to vision loss as key primary endpoints. They feel like these are endpoints that could certainly give us full approval. And so these additional endpoints could be helpful as the data evolves, for example, at an interim analysis. With respect to your second question around the adverse events, I have to tell you, although not shown in the slide deck today, we've actually collected data from all of our monotherapy trials with darovasertib, because we wanted to get a good comprehensive overview of the safety profile. So looking at the initial Novartis phase 1 trial, as well as our 01 study, and then including patients who were in the neoadjuvant trials, both run by our investigator-sponsored study in Australia, as well as our own 009 study, the grade three or greater adverse event rate is extremely low. I mean, the highest adverse event was 5.7%. Everything else was below that. So to be quite honest, as a monotherapy, darovasertib's very well tolerated. SAEs, or Serious Adverse Events, are extremely uncommon. Discontinuation due to adverse events is low. So I got to be quite frank, there's really not a lot to talk about there, to be honest. There's just, you know, case examples of adverse events, but overall, extremely well tolerated. And if you look at the kind of impact that we're having in terms of antitumor activity, I think that just speaks to the fact that we're definitely on the key driver. You know, we're basically putting the brakes on the gas pedal, which is protein kinase C, and we're doing it in a way that patients tolerate very well, which is exciting. Thanks so much for taking our questions. Thanks, Anupam. So our next question comes from Maury Raycroft at Jefferies. Please go ahead, Maury. Hi, good morning. Congrats on the update, and thanks for taking my questions. For the registrational study, what are the landmark times for measuring eye preservation and vision loss, respectively? Or is this something that is still being determined with FDA, and we'll learn more about this later this year? I guess, how could that be operationalized in the study? Darrin, you want to take that? Landmark is probably not the right term because landmark implies that, you know, we're gonna look at specific times. But from the perspective of what we plan to do is an interim analysis, obviously, and then a final analysis, and then at the interim, we'll be looking at time to vision loss. Looking at this patient population that we plan to enroll, this is gonna be a patient population that's gonna be exposed to a significant amount of radiation, which means their likelihood of being blind three years down the road, that is legally blind, is actually quite high. Then if you look at the fact that we're gonna look at a visual outcome, something like loss of 15 letters, that can happen much sooner before someone goes blind. It allows us the opportunity to be able to look at the time of visual decrement in the control group, which should be rather robust, and compare that to the treatment arm, which we believe will have a significant impact because of the tumor shrinkage and the radiation reduction that Dr. Shields talked about. With that, you know, we'll be able to get an early read, and I think the enucleation part speaks to itself. It's very likely, very early, we're gonna see lots of eyes saved. In addition, based on looking at, you know, fifteen best-corrected visual acuity, fifteen letters, it's likely we'll be able to get a good early view on visual decrement as well, and that'll put us in great place at the first interim analysis, which would be approximately two years down the road. Does that answer your question? Got it. Makes sense. Yeah. Yeah, that makes sense. And then for measuring and controlling radiation reduction in the registrational study, can you talk about what worked and what didn't work in the phase two, and what is the most likely scenario for how you'll operationalize that in the phase three? Just say that again. Could you say that one more time? For measuring radiation reduction and controlling radiation reduction in the registrational study. Yeah, so we did that with simulation, right? So we did that at baseline, had patients simulated, and then posttreatment, had them simulated again. Again, if radiation reduction is gonna be something that we look at very, very carefully, we'd have to do the same. You know, whether we do it independently or not, I think is still to be determined. Currently, it is being done independently from the sites, so we have sort of an unbiased view of what at least our central reviewer sees in terms of what they think the radiation dose would be prior to neoadjuvant therapy and what the radiation dose would be post-neoadjuvant therapy. So we're still thinking about what level of scrutiny to put on that for this, since it's just gonna be a secondary endpoint. We know what the key primaries are. Yeah, we would be using simulation pre- and post-therapy, just like we're doing in the 009 study. Got it. Understood. Thanks for taking my questions. ... Thanks for the questions, Maury. Our next question comes from Gregory Renza. Great, thanks. Good morning, Yujiro and team. Congrats on the updates, and thanks for taking my questions. Yujiro, maybe a question for Dr. Shields, if Dr. Shields is still on the line. Just thinking about the adoption and the use of darovasertib, what percentage of your uveal melanoma patients do you think the percentage just in clinical practice would you and others prescribe darovasertib if potentially approved? And just curious, just given that a fraction of the slow-progressing patients are certainly put under monitoring, at what point during the disease course would you think a patient should be put on daro, just based on the benefit risk that you've seen from the data so far? Great, great question, Greig. Dr. Shields? Yes, thank you. Thanks for the question. I honestly think that there will be fairly universal adoption of this medication. It's not been difficult for us to enter patients on the trial currently, because patients understand that if we go to enucleation, they lose their eye, and that's it. Or if we go to radiation, they're getting a big dose of radiation, and that's likely to cause vision loss. So currently, about 20% of patients that have uveal melanoma wind up with enucleation, and 80% with plaque radiotherapy. And I think patients will understand the importance of the new medication, whether it's used for three or six months to shrink tumor and provide them with better outcomes. But I also think there's an underlying enthusiasm from ocular oncologists and medical oncologists that we might be reducing metastatic disease, which is really the ultimate goal. Great, that's very helpful. But, really appreciate the color, and thank you, Yujiro, for... Congrats again. Yeah. Thank you, Greig. Thanks for the questions, Greig. Our next question comes from Andy Berens at Leerink. Please go ahead, Andy. Hi, thanks, and congrats on the data and the progress. Just a couple from me. If you guys can do an interim look using OR, would you also have to show a trend in event-free survival? Could that trend be non-inferior, and if so, how long do you think the agency would wanna see this trend maintained to have conviction in the interim results? And then you also mentioned in the press release, earlier stage uveal melanoma. Are you referring to patients that have very early disease, like indeterminate lesions? Will they actually be enrolled in the trial? And if not, how much does that impact the addressable market? And then I have two for Dr. Shields, too, if that's okay. Sure. Darrin, do you wanna take the first portion? Yeah, let me think. So, the first one was because I got confused listening to the second one about who's gonna get enrolled. The first one was about the endpoint. So remember, the primary endpoints are enucleation prevention and time to visual detriment, right? So overall response isn't the primary endpoint. So think about it this way, you know, where we'd like to be as the trial reads out its first interim is we'd like to have a significant number of eyes saved, eyes saved. As you've seen, it's 60% or greater, so that's wonderful. So at the first interim, we have saved 60% of eyes. We've seen, hopefully at that time, some visual preservation, so there'll be some evidence of that. And then additional secondary endpoints that go along with that would be something like, you know, we could say, "Hey, look, you know, the time to macular edema seemed to be longer in those patients who got neoadjuvant therapy. The tumors shrank significantly in those who got neoadjuvant therapy. If we decide to simulate radiation doses, the amount of radiation those patients got was reduced." So really, it's a constellation of things. And with respect to event-free survival, the great news is, I think, in the FDA's wisdom, the way we will design the trial is, you know, we don't have to show superiority with respect to event-free survival. We don't need to show non-inferiority. I think the idea is to make sure that we have enough events at the time that we read this out to show that we're not providing any detriment to patients' outcome by providing neoadjuvant therapy. That's the key. I mean, I think, to the credit of the FDA, you know, they wanna make sure that, you know, if you're delaying, you know, radiation therapy, if you're delaying definitive treatment to the eye, you're not having an overall detriment to the patient, and to their credit, they recognize this is, you know, an orphan indication, and these trials could be rather big, if you power them to show superiority or non-inferiority. It was felt that, I think, the results were significant enough that, you know, being able to show with a hazard ratio that implies that there's no harm, in addition to significant outcomes, such as saving the eyes and reducing the amount of patients who you either lose vision or become legally blind, that would be a great position to be in. That would be great for patients, and it would imply really no harm to patients, and all of that together would be a path forward to get this to patients as quickly as possible. Does that answer your first question? Yeah, just on the definition of an event, would enucleation count as an event, or will that be excluded? No, no, no. Yeah, right. Yeah, I think this would be survival related. Yeah. So, you know, additional metastasis- Local or distal relapse is kind of what the main thing is. Okay. Got it. Thank you. Andy, I'll just quickly answer your second question. I think you had asked about some of the smaller ocular tumors. So I think there, perhaps what you're referencing, which was noted in the release, is that, you know, here we'll likely target to study the high-risk metastatic group, primarily because in that population, we anticipate we'll get an earlier readout on endpoints such as EFS. However, as part of the FDA meeting, at least our understanding of that meeting, what there would be potential openness to considering a broader label to also include these lower risk and medium metastatic risk patients. So that's what that was referencing. Then I think your third, you had some questions for Dr. Shields, so we'll let you ask those. Yeah. I was just wondering, in the patients that had enucleation converted to brachy and the eye was preserved, wondering what you would expect the longer-term outcome to be in these patients? Would they likely avoid it in the future, or would most of them eventually have their eye removed? And then just in the context of other options that could be available in the future, like Aura Biosciences' bel-sar, I was just wondering how she sees this intervention could fit into the treatment paradigm versus what they're targeting. Yeah. So, Andy, you know, on the second one, I'd just sort of like Dr. Shields to just sort of focus on our update. I think just as a practice, probably better not to talk about other programs for this purpose. But Dr. Shields, do you wanna maybe address the first question? Sure. Yes. Right. The conversion of enucleation down to smaller size so that we can save the eye with plaque brachytherapy is the reality. You know, in this study, 61% of patients had their eye saved, and yes, it is lasting. So when we do plaque brachytherapy for uveal melanoma, we give an apex dose that is lasting, and in our hands, we have maybe only 1% of patients show recurrence. So we do think it's going to be lasting, and there was a big study done called the Collaborative Ocular Melanoma Study. It was done in the nineteen eighties, nineteen nineties, and it was a comparison of enucleation versus plaque brachytherapy. We found, in the long run, the risk for metastatic disease was no worse in either arm, so that plaque brachytherapy, if you can shrink a tumor down to the point that you can treat it with plaque brachytherapy, you can provide the patient equivalent prognosis. Okay. That's very helpful. Thanks, and congrats again. Thanks for the question, Andy. So our next question comes from Yigal Nochomovitz at Citi. Please go ahead, Yigal. Yeah, hi, thank you. Could you just clarify, Dr. Shields, if you wouldn't mind, you mentioned the simulation of the radiation dose before daro and then after daro. I'm just curious why it wasn't compared to the actual dose delivered post-daro versus the simulated dose? I can- Yes. I can take... Do you want me to take that, Carol? Go ahead. Mm-hmm. Yes, go ahead. Yeah, essentially, you know, the sites do their own simulation, but what we wanted to do is have sort of it independently reviewed, you know, using the Eye Physics software we had. And then, you know, it's kind of like when you do response, right? Obviously, you know, in some of these registration trials, particularly single-arm phase 2s, you get blind, independent central review. This was just a way to get a view of what an independent reader would have argued that the radiation dose would have been before and after therapy. But obviously, if you're gonna use that as a key endpoint, like it would be, if we were gonna use it as a primary endpoint, you'd wanna have both site and blind independent central review results at the same time. But since it's a secondary here, we're likely to go with one or the other. Okay, thank you. And then can you just confirm that in the patients that were spared enucleation, that all of them achieved at least the 20%, or greater tumor shrinkage that was considered clinically meaningful by your advisory board? If you look at the graphic that was provided, you can see that there are little hatched arrows above each one of those bars in the waterfall plot that shows you who are the folks that require enucleation. You can see that the vast majority of them fall under the 20% shrinkage point. There were a few exceptions that we had less than 20% shrinkage and were spared enucleation, but for the most part. You know, it's the same with radiation reduction. There's always exceptions to the rule, but the preponderance of the results that we've seen thus far imply, at least at this point in time, that a minus 20% or a 20% reduction in tumor measurements correlate well with both radiation reduction and eye preservation. Yigal, the slide Darrin's referring to, slide 19, there are three patients that were below the 20% that had their eye. See See one, one right below that 20% line. Okay, thanks. And then with the discussion with the FDA on EFS, did you come to an agreement on the number of events that would require to trigger the interim analysis? Because I recall for Kimmtrak, that took much longer. I think it was over five years before they got to an answer. So the number of events thus far is still being constructed as we put together the final protocol and the synopsis. So, you know, I don't wanna dig into exquisite details, but suffice it to say, like I said, at that first interim analysis of two years, I mean, doesn't take. It's not hard to imagine. We're gonna have a lot of eyes saved? The answer is, if the data continues to look like it looks now, the answer is yes. Are we gonna have significant improvement in visual outcomes at that period of time if we're looking at best corrective visual acuity, 15 letters? The answer is probably yes. You know, I think at the end of the day, it's all gonna be about how mature the data is, and is required by the FDA on EFS, and we don't have a lot of clarity, but I can tell you this: I don't think it's gonna be, you know, a huge amount. I think that they're gonna be reasonable, knowing that this is having the kind of impact that Carol talked about, you know, just a major impact on patients. And, of course, they'll want us to follow it over time, but, you know, that first interim analysis will allow us to have that discussion with them, look at the number of events that happened. And remember, this is gonna be a high-risk patient population, right? So high-risk patient population means a significant proportion are going to relapse, you know, in that two- to three-year time period. So, you know, It gives us a great opportunity, I think, at that first interim to hopefully do everything that we see in the 009 t rial, which is, you know, save the eyes, preserve the vision, do this without harm to patients, and with that, you know, we'll be in good shape. But, you know, I think we're doing everything we can in terms of designing the trial to get the outcome as quickly as possible. Yeah, and I think you go there, maybe just end with, you know, at least as it relates to EFS, right? I think this was, at least we think, best-case scenario, right? Secondary endpoint, no detriment, and that's why we emphasize if we focus on the high-risk population, you know, at least we would anticipate we'd be able to get that initial read, sooner. Great. Thank you very much. Sure. Thanks for the question. Our next question comes from Matt Biegler at Oppenheimer. Please go ahead, Matt. Hey, good morning, guys. I also had a question on timelines, and kind of tagging on to you guys here, because Kimmtrak's adjuvant trial, I think, is estimated on ClinicalTrials.gov at around eight years. So it sounds to me like from the previous question, that you think that you can do it faster based on the degree of benefit that you're seeing here, and obviously, we're gonna get that interim look at two years. And then I also had a question- Hang on. Let me stop you there. Just hang on a second, 'cause you said something really important that I may have missed from the last question, which is, you're talking about adjuvant, right? So you're talking about the Kimmtrak adjuvant trial. We're talking about neoadjuvant. We're in a totally different ballgame here, right? The adjuvant is a whole different kettle of fish. And as you know, we're very interested in the adjuvant setting, too, and we're looking at that, but those timelines are very, very different, so I wouldn't get those confused with the neoadjuvant setting that I've just described. Very important. You're right, the adjuvant setting could indeed take longer depending on how you do it. And again, it depends on the patients you enroll. Kimmtrak is enrolling patients, I believe they're all stage three. Some of the early stage three patients may be not metastasizing for a bit longer than some of the others. But if you really refine the patient population, you know, for the Class 2s, you know, the BAP1 positives, et cetera, the ones that are gonna relapse early, your timelines can vary. But again, don't get the adjuvant confused with the neoadjuvant. The timelines are very, very different. Neoadjuvant can happen much faster. Mm-hmm. Yeah, and maybe, Matt, there, I'll be brief, but if you just sort of break it apart, right? I think what Darrin's referring to, obviously, typically for neoadjuvant, in this case, we're talking about event-free survival, right? For adjuvant, it's different. It's relapse-free survival. So those are obviously not exactly the same. Second, typically for adjuvant trials there, you know, as a primary, would the need to show superiority on RFS, and again, there, that directly impacts the hazard ratio, therefore, the amount of patients you have to enroll, as well. So that's why we had, you know, I think, tried to emphasize around no detriment to EFS as a secondary is, we think, significant, because that would obviously dramatically change what we would need in terms of statistical thresholds, therefore, how much we would have to enroll. You know, we have modeled similar ranges, Matt, as you mentioned, for adjuvant, but again, as neoadjuvant, you're talking different endpoints, different setup. Got it. I think you actually just answered my second question for Dr. Shields, so I'll jump back in the queue. Thanks, guys. Sure. Thank you for the question. Our next question comes from Charles Zhu at LifeSci Capital. Please go ahead, Charles. Hey, good morning, everyone. Thanks for providing the update, and congrats on all the progress. One clarifying question here: is vision loss, as it pertains as a regulatory endpoint, a binary outcome based on whether or not the patient is legally blind, or is there a spectrum to consider based on visual acuity measures, like letters or remaining letters the patient is able to visualize? And how do things like peripheral vision factor into this, if at all? Thank you. Yeah, first, maybe I'll first start there. So, you know, here, Charles, just to be really specific, so this would be time to vision loss, right? And you would have that readout in a randomized fashion versus your control arm. But, Darrin, do you wanna answer the rest of that? Yeah. Yeah, and Charles, to your point, I mean, the 20/200 vision legally blind is different than a visual decrement of fifteen letters, right? And so obviously, the time for you to go legally blind is gonna be longer than the time that perhaps you lose fifteen letters or some degree of visual loss. And so we're gonna define how we are going to measure that. We think fifteen letters is good, but we may wanna do something similar to that. But essentially, it's some degree of visual loss over that period of time of two years that can be measured between the two groups very accurately to show that level of visual decrement, which is not necessarily blindness, occurs in the control arm, but is preserved in the treatment arm. Got it. Great. And perhaps for my next question, I think a prior analyst asked this as well. Maybe I'll ask it in a slightly different way, but it feels like your intended registrational trial, you know, could have perhaps a bit of a more focused patient enrollment baseline criteria relative to how broad of a label you could potentially obtain. So maybe question for not only the company, but also for Dr. Shields. You know, how would you think about the data from the registrational trial being applied in potentially treating patients as part of the broader label, but maybe may not have fallen into the baseline characteristics of the registrational trial? Thank you. Yeah. So obviously, maybe just quickly on the label part, I mean, Charles, obviously, we just want to be thoughtful here just with our dialogue with the FDA, and obviously, all of these items as it relates to that would ultimately be a review issue. You know, we noted, as we understood it from the Type C meeting with the FDA, I think the piece, Dr. Shields, just I suppose around clinical practice, anything there you could add? I think in clinical practice, the label will definitely include small, medium, and large, I would estimate. We might see less benefit for small melanoma, but if we look to metastatic outcomes, patients with small melanoma can develop metastatic disease, so there might be a role for it, even with the small melanoma. I'm not sure how it would play into the indeterminate lesions. Those are the query: Is this really a melanoma, or is it not? Currently, we wait until it shows evidence of growth nowadays, and, you know, in some ways, that's very unsettling for a patient to leave the office and say, "Wow, they don't know if it's a melanoma, and now they're making me wait." So there may be a subset of patients in indeterminate lesions who would be very interested in a medication because we have nothing else. Yeah. Tha- Got it. Thanks for that description, Dr. Shields, and that's where, Charles, you know, we had highlighted this component around the small ocular tumors in my section, which obviously impacts, you know, potential total prevalence. Got it. Great. Thank you. One last quick clarifying check-the-box from me. I may have missed this, but have you provided the split amongst these 400 patients between Cohort One and Cohort Two? And I'd assume there's an opportunity for separate filings for each of these discrete patient populations, but want to clarify that. Darren? A couple of things. You know, the idea will be it'll be, you know, driven by the power of the study, right? So the sample size will be related to the statistical design, but it's likely that there'll be a fairly even split between the two. That's the first thing. And your second question, Charles, was what again? whether or not there'd be an opportunity for separate filings- Oh. ... one specifically to enucleation, the other specifically for brachytherapy cohort. Yeah. Well, you know, it kind of depends on how they read out, right? The enucleation is likely to, at the two-year time point, be very, very significant, I would think, based on what we've seen so far, and so then it's just a matter of what's, what's going on with the vision on the, on the enucleation side. You know, our thought process is we'd have the opportunity to get both at the same time, you know. And it depends on how it reads out, and I guess we'll have to deal with that when we get there. But I think the objective is that first interim, we should have set ourselves up by choosing the appropriate patient population to get full readouts on both at the same time. That would be the desired endpoint, of course. Great. Thank you for taking all my questions, and congrats again. Thank you, Charles. Yes, thanks for the questions, Charles. Our next question comes from Justin Zelin at BTIG. Please go ahead, Justin. Thanks for taking our questions, and congrats on the progress here. Can you hear me okay? Yes. Yep, we can hear you, Justin. Great. Just a few questions. Dr. Shields mentioned the importance of reducing progression, metastasis in this population. Just a few questions surrounding that. Would you have any data thus far to suggest that daro is reducing metastasis, or is it too immature yet to present data like that? Second, just clarifying, would metastasis or progression be considered to be an event? And maybe if Dr. Shields has any data on when typically uveal melanoma high-risk patients do metastasize, just the timeline of that, that would be helpful. Thank you. Yeah, so I think to the second question, would metastasis be considered an event? That answer is yes. Darrin, do you wanna take the first portion there? Yeah. What was the first one again, though? ... Yeah, the first question was just if you had any data to support daro reducing metastasis, or is it maybe too immature? No, well, you know, the problem there is you need a control arm, right? And so we haven't done a randomized study, so we can look. We haven't had a lot of that thus far, but again, without a control arm, it's hard to say. But, I mean, as Carol, Dr. Shields pointed out, we're, we're having significant tumor shrinkage, right? And, you know, we're, we're dealing with the primary driver of the disease. So I, I think, you know, treating folks both in the neoadjuvant and adjuvant setting has some great appeal to prevent metastases. But do we have any direct evidence of that at the moment? The answer is no, simply because you need a control arm to see that, to be, to be definitive. Does that make sense? Yeah, that makes sense. And I don't know if Dr. Shields is able to comment on typically, how quickly a high-risk uveal melanoma patients typically metastasize, or if it's, Yeah, I was, I was gonna say metastatic disease typically occurs, depending upon the tumor size, between two and seven years after the diagnosis of melanoma. But metastatic disease closely correlates to tumor size. We did a big study years ago on several thousand patients and found that every millimeter a melanoma gets larger adds an increase of 5% risk for metastatic disease at ten years. So just to give you an example, a 10-millimeter-thick melanoma has a 50% rate of metastatic disease at ten years, whereas a 2-millimeter-thick melanoma has only a 10% rate of metastasis at ten years. So you can only imagine that the response that we're seeing in the eye will somehow, maybe not one to one, but somehow correlate with reduction in metastatic disease. But I don't know of any data that's out there yet. The only thing I would add to what Dr. Shields said is we also can look at cytogenetics and gene expression profiling that tells us, and we know that Class 2s, for example, or patients with monosomy 3, you know, a few studies have shown that, you know, folks, you know, the median time to metastases or metastasis-free survival is about three years. So there are patients, if you choose them, Class 2s, BAP1 positives, PRAME positives, monosomy 3, maybe extra chromosome 8, et cetera. So there's a number of features out there that suggest a high-risk patient population that metastasize earlier, and that's kind of why we talked about the design that we have, right? With the going at the high-risk patients, because as you know, the lower risk patients, perhaps with the smaller tumors or with the Class 1A, for example, by gene expression profiling, they could take a very long time to read out. We obviously want to get this opportunity to patients as rapidly as possible, and that's why we've angled towards the higher risk patient population. Fortunately, the FDA was open-minded and suggested that, you know, if you were to show no harm in a high-risk patient population, why would you think there'd be any harm in a lower risk patient population? There shouldn't be. So I think that's why they were open-minded about a broader label, even if we study just the high-risk folks that are likely to have an event early. Great, thanks for the question, Justin. Our next question comes from Graig Suvannavejh at Mizuho. Please go ahead, Graig. Greg, I don't know if you have a question or you might be on mute. Okay, Greg, please press star six to unmute. Hmm. Seems like he's stuck. And maybe, Tara, maybe we can go to the next question. Yeah, we'll go to the next analyst while Greg figures out the mute. So our next question comes from Tim Chiang at Capital One Securities. Please go ahead, Tim. Oh, thanks. Yujiro, I wanted to ask you just about the timing for the start of the pivotal study. When do you think that the study could possibly be initiated? I know it seems like your discussions with the FDA are still ongoing, but you know, one, you know, what do you still need to sort of lock down with the FDA before you can initiate this study? And two, how long would it take to actually enroll the 400 patients that you're targeting? Yeah, thanks for the question, Tim. So in terms of the timing, yeah, the primary, I would say, objective here with the FDA is now to finalize the clinical protocol. So, you know, we would hope we can do that in, in roughly a quarter, you know, perhaps an additional quarter to, to get the study going. Obviously, you know, plus or minus, but I think that's sort of bigger picture. In terms of time to enroll, you know, here, what we've estimated, at least based on our, our existing projections, roughly 400 patients to enroll. We are seeing what we think is robust demand in the neoadjuvant setting. Darrin, there, do you wanna just give a high level on your thoughts on that? ... Which point, Yujiro? I'm sorry, I got- In terms of study enrollment or- Oh the neoadjuvant- Yeah, yes. So- Try to enroll more patients. Let me just say this. As you know, we're enrolling in the neoadjuvant trial. We're also enrolling in the registration trial, and as Carol pointed out, you know, when you have a therapy that's this effective, it's the patients know about it. They're very intrigued, they're interested, they wanna get on trial, and I'm very happy to tell you that both of those studies are enrolling ahead of schedule very, very rapidly. And I think, you know, the fact that we're providing this kind of benefit to patients, I see, you know, us having the ability to enroll the patients in a very timely manner. We do have a large number of sites globally, Australia, Europe, Canada, US, and they're really enrolling well. I'm not really so worried, to be honest. You know, I have to admit, when I first came to IDEAYA, I was like: Ooh, you know, this might be tough to enroll. But it's amazing when you have a therapy that really works, how easy it is to get patients to be interested and get on study. You know, with investigators like Dr. Shields, and there are a number of ocular oncologists that we work with, some of the leaders in the field that are highly enthusiastic about this therapy. For that reason, I think enrollment is really not a major concern whatsoever. At least it hasn't been thus far. Okay, great. Thank you very much. Yeah. Thanks for the question, Tim. So our next question comes from Ben Burnett at Stifel. Please go ahead, Ben. Fantastic. Thank you. I was wondering if you could maybe talk about the duration of treatment you're seeing in the neoadjuvant setting, and I guess what will be specified in the phase III protocol, just in terms of dosing daro in that setting? And also curious if there's opportunities for the patient to continue therapy thereafter in the adjuvant setting. Yeah, I think there, Ben, just as a reminder, you know, existing most of those patients were put on trial when the protocol duration was up to six months. Obviously, that was amended, and I think we're still learning that in terms of that question on duration. But Darrin, do you wanna maybe give- Yeah, I mean, I think, yeah, you've kinda nailed it. It's, you know, we have a number of patients who get out, you know, up to six months, and we have investigators that wanna continue therapy because the tumor is continuing to shrink. I think we have some evidence of benefit beyond six months. It's continuing to grow. So I think, you know, the way we hope to treat patients is until maximum benefit, meaning if the tumor is still shrinking and you think they can benefit, you know, why stop? On the other hand, if you've reached a point of stability, maybe it's time to take the patient to the primary therapy. And then with respect to your, your question about adjuvant, you know, for the registration trial, you know, adjuvant won't be part of that study. We'll look to address adjuvant in a different setting. But for the registration, neoadjuvant phase III trial, that won't include adjuvant treatment. Okay. Thank you. And if I could just ask maybe kind of another timing question. How long does it take for vision preservation to sort of be clear? I guess focusing on the sort of brachytherapy cohort, it's my understanding that radiation effects on vision can take kinda time to materialize. So just trying to get a sense for how much follow-up time you would need sort of to assess vision preservation. So- Yeah, I think... Go ahead. Sorry. Sorry. Yeah, no, I think there, Ben, that's why we emphasize the time to vision loss, because we do think that would hopefully give us an earlier read on that, and as well as what Darrin mentioned earlier about, you know, focusing on these patients with a high risk, because we would anticipate those patients in the control arm would pretty much lose their vision. So obviously, that would all impact the specific time to vision loss readout. But, Darrin, anything additional? Yeah, I mean, and Carol, correct me if I'm wrong, but the way I see it is, listen, the patients that we plan to enroll in this study are gonna get a significant dose of radiation, which means at the three-year time point, you know, a significant proportion of those will have, you know, 20/200 vision, which is legal blindness. And so if we looked at its earlier time point, looking at 15 letters, which is not blindness, but it's obviously a decrement in vision, you would think at the two-year time point, you know, you if you're having as big an impact as you think, you're likely to see something, and that's why I think we're feeling pretty comfortable with sort of that two-year time point. Because we're not looking at legally blind or legal blindness, because we know that's likely to come down the road, but obviously, there's gonna be detriment, significant detriment before we actually get to that point that we hope we can pick up at an early time point, so I think that should explain to you why we have some degree of confidence that, you know, if we really are shrinking tumors significantly, we are really reducing radiation doses by that 30%-50% or more, depending on how long patients are on therapy. You have to imagine that, you know, the degree of visual decrement, which is not, you know, as bad as 20/200, is gonna become evident, and we'll be able to measure that at a reasonable time down the road. Okay. Thank you very much. I appreciate it. Yep. Thanks for the question, Ben. Our next question comes from Corinne Jenkins at Goldman Sachs. Please go ahead, Corinne. ... Good morning. I think you mentioned that you would anticipate timely enrollment, but, in the phase 3 study or in the registrational trial, but would you anticipate any difference between the pace of enrollment in the enucleation patients versus the plaque brachytherapy patients? And then one from, for the doctor, I guess, how are you thinking about kind of like stopping thresholds for therapy in these patients? For example, how long would you wait to see tumor shrinkage before you move on? And how long would you look to see stabilization before kind of deciding to go forward with a plaque brachytherapy? Thanks. Darrin, you want to take the first question? Yeah. as it relates to cadence of enrollment for Yeah, I can take that. Yeah. So it goes like this: it's kind of interesting, you know, for the 0O9 trial, you know, with as Dr. Shields pointed out at the beginning, you know, the idea that, you know, maybe 20% of patients get enucleation and 80% of patients get plaque brachytherapy, those are general numbers. You know, they can vary between the US and ex-US countries. The rates are a little bit different, but, you know, that's sort of in the range. If you just take that at face value, you'd think that, oh, I'm gonna enroll a lot of plaque brachytherapy patients, and there's gonna be a fewer number of enucleation patients. But we've actually... And the way we started this study, we actually saw the opposite. We saw way more enucleation patients at the beginning, but now the plaque brachytherapy patients have caught up, and we're about fifty-fifty. So actually, because I think the impact is so huge, you know, saving the eye, I all I can tell you is, as of today, we've had an equal split between the two patient populations. Will that continue with a study of four hundred patients? I don't know for sure, but I suspect that based on what we're seeing and the impact that we're having, the plaque brachytherapy, excuse me, the enucleation group isn't gonna lag that far behind, despite the fact, you know, it seems to be less common. But that's where we are today. Yeah. Dr. Shields, for the second question. Yeah, and I'll just add on to what Darrin said. If you look at Europe, they use a different radioactive device than we use in the United States. They use ruthenium, we use iodine, and ruthenium can only irradiate up to, like, say, six millimeters in thickness, so they may have more enucleations than we have in the US, so that might kind of compound it. But anyways, your question to me was, like, when do we stop the treatment? Like, what is our threshold? So by design, you know, everyone receives two doses of the medication, and then we are free to stop the therapy when we see no further reduction in thickness. I would say, in our clinic, if we would have, you know, no change in ultrasound thickness for two consecutive visits, we would start talking about plaque radiation rather than continuing on the medication. Yeah. We can go all the way up to 12 months currently. Thank you. Mm-hmm. Thank you for the questions, Corinne. So Greg sent us his question, so I'm gonna read them out loud. His first question is: when will you get clarity from the FDA on the potential other endpoints? Darrin, do you want to- Yeah, so that's gonna come in the process of reviewing the synopsis protocol. You know, these are what I've described in the presentation and what the questions are, endpoints of clinical relevance, I think, of importance for the study. You know how they'll actually be mapped out in terms of the statistical design, et cetera. That's what's still in progress as the FDA reviews our synopsis protocol. Yeah, and maybe here also, just on that question, you know, I think here we would just emphasize the timing for the primary endpoint data readout, and I think ultimately on the no detriment for EFS, that even with the surrogate endpoint at response rate, you know, I think we've had discussions internally, the timing of those scenarios could end up being even with a response rate criteria defined and accepted where we move forward, that we could end up getting full approval at a very similar timeframe as the use of a surrogate endpoint, like response rates. I don't know, Darrin, anything else there? No, I mean, I think it's key to just recognize that, you know, enucleation is considered, you know, a full approval endpoint, at least based on the initial discussion we had at the Type C meeting. Same is true for, you know, vision preservation. So there wouldn't be a need for an accelerated approval if you're getting an approval based on those endpoints. But again, I'm painting the picture that, you know, we're gonna have those as primary endpoints, which is great, but whatever supportive data that we could have, I mean, you know, we're gonna have response, we're gonna have radiation reduction, perhaps we're gonna have time to macular edema, all key and clinically relevant endpoints. And so if we look at EFS, and, you know, I don't know what the threshold is for the number of events that the FDA is gonna need in order to give the nod, but if you think about it, if the data's immature and all of that other data looks extremely positive, you know, perhaps there'd be an opportunity there to say, "Okay, we're gonna..." The FDA may say, "Hey, let's continue to watch this over time, but in the meantime, let's get this opportunity to patients in the short term," and how they would actually do that would, you know, need to be negotiated, et cetera. But I, you know, to the FDA's credit, I think they recognize that we're looking at a great opportunity for patients here. They're very willing to work with us to work through, you know, a very challenging trial design, to be quite honest. Nobody's done this before. We're sort of the first. As Dr. Shields pointed out, this is changing the field. You know, when you change the management of a disease, you completely turn it upside down for a therapy that has this kind of impact. You're breaking new ground, and with new ground comes challenges, and they seem very open in their willingness to work with us to come up with the solutions. So now what we have to do is get the protocol synopsis together, talk about it a bit more, and hopefully we'll come to a really good place that everybody feels like we're really giving the darovasertib the best opportunity to not only show success, but to get to patients as quickly as possible. Great. Tara, next, was there a second question? Yes, this one's for Dr. Shields. So in your opinion, what would you say is the likelihood of darovasertib showing a statistically positive benefit on, A, the enucleation, and, B, the preservation of vision endpoints at the interim analysis? So Dr. Shields, I think maybe if I could just sort of step in on this one. I think we probably want to just stay a little bit away from trying to future predict on some of these outcomes. Yeah. So I think all we could say at this point is, you know, we have about, you know, roughly 50 patients worth of data. You know, we feel good about where the eye preservation rate is. As was noted in the press release, what was noted in our FDA briefing book was, you know, hopefully being able to achieve at least a lower bound of 10% on a 95% confidence interval. So I think based on that, I think hopefully we're in a good spot. And then on the vision piece, I think Dr. Shields went through some of that data. So hopefully that answers that one. Darrin, anything else here? No, yeah, I hate to speculate, but obviously the data speaks for itself. All you have to do is look at the data that we have. I mean, it's just, it's quite striking, and Dr. Shields pointed that out when she gave her perspective, and I think that just puts us in a great position, you know, to get this to patients. We just have to do the study and execute it, and that's what we're working on now. Great. Thanks for those questions. Tara, do we have anybody else on the queue? Nope. That concludes our Q&A session. Great. Well, thank you so much for everyone to participate in this webcast and then to dial in. And again, thank you so much, Dr. Shields, for your participation today.