I'd now like to begin our webcast event. As a reminder, all participants are in a listen-only mode. Following today's KOL discussion, there will be a Q&A with analysts. Instructions will be provided at that time for analysts to ask a question. A replay of today's event will be available on the investor section of the LeonaBio website. I would now like to turn the call over to Mark Litton, President and CEO of LeonaBio. Thank you, Alyssa. Good afternoon, everyone. I'm Mark Litton, President and CEO of LeonaBio. On behalf of our entire team, thank you for joining us today for a discussion on Modulation and Combination: Unlocking the Potential for lasofoxifene to Transform the Standard of Care in metastatic breast cancer. Next slide, please. We are pleased today to be joined by two world-leading breast cancer physicians and researchers who sit at the forefront of clinical care, translational science, and drug development. Together, we'll discuss the rapidly evolving treatment landscape in ER-positive metastatic breast cancer, the challenges patients continue to face, particularly those with endocrine-resistant disease, and the opportunity we believe lasofoxifene represents within this shifting paradigm. Next slide. Before we begin, I'd like to remind you that during today's call, we will be making forward-looking statements. Such forward-looking statements involve risks and uncertainties. Please refer to our filings with the SEC or on the investor section of the LeonaBio website for more information concerning the risk factors that could affect the company. I'd like to note that the views expressed by our physician experts are their own and do not necessarily reflect the views of the company. Next slide, please. For those of you newer to our story, at the end of 2025, we announced the license of development and commercialization rights to lasofoxifene in a phase III clinical program for metastatic breast cancer. This transaction was a pivotal moment for our company, diversifying our pipeline with a late-stage asset and positioning LeonaBio squarely at the intersection of endocrine biology, precision medicine, and combination therapy strategies. That transformation prompted our rebrand to LeonaBio, a name grounded in leadership, resilience, and innovation, qualities that define our mission to deliver meaningful advance for patients facing serious diseases with limited options. That mission is not aspirational. It guides our strategy, our investment decisions, and our urgency because to help patients with metastatic breast cancer, time really matters. Among patients with metastatic breast cancer, ER-positive disease remains the most common subtype, accounting for roughly 70% of all metastatic breast cancer cases. Despite meaningful progress over the last decade, endocrine resistance remains inevitable for many patients. With ESR1 mutations emerging as a key driver of endocrine failure following AI therapy and CDK4/6 inhibitor therapy. At the same time, the treatment landscape is evolving rapidly. There are new oral SERDs, PROTACs, and combination regimens are advancing. Currently, there are biomarker-driven strategies that are increasingly shaping clinical decision-making. This evolution underscores something critical. The field recognizes that better estrogen receptor modulation, alone and in rational combination, remains fundamental to improving our outcomes. Next slide, please. The breast cancer market is approximately $55 billion, with the U.S. 2L breast cancer segment alone exceeding $5+ billion annually. A substantial portion of these patients harbor ESR1 mutations. With testing now routine, this represents a significant unmet need and commercial opportunity. Against this backdrop, the global ER-positive metastatic breast cancer market is expected to grow, driven by longer treatment durations, combination approaches, and continued unmet need for differentiated therapies. We believe lasofoxifene, with its unique modulating receptor binding properties, activity in the ESR1 mutant disease, and compatibility with combination strategies, is well-positioned to succeed within this landscape. Next slide, please. Today's discussion is designed to go beyond headlines and delve into how clinicians think about resistance, sequencing, and combinations in real-world practice and where lasofoxifene may fit as a standard of care in this space. We are privileged to be joined by two outstanding physician scientists. Dr. Matthew Goetz is a professor of oncology and pharmacology at the Mayo Clinic in Rochester, Minnesota, where he serves as director of Breast Cancer SPORE and is a national leader in estrogen receptor-positive breast cancer and endocrine resistance. He has authored more than 300 peer-reviewed publications and has played a central role in advancing translational and genome-guided therapies for hormone-driven breast cancer. Dr. Seth Wander is a medical oncologist at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School. He serves as director of precision medicine at the Henri and Belinda Termeer Center for Targeted Therapies and director of translational research for the Breast Cancer Oncology Program. His research focuses on mechanisms of endocrine resistance and the development of molecularly informed treatment strategies, and he has authored more than 70 peer-reviewed publications in precision oncology. Moderating today's discussion is David Portmann, who truly embodies the long-term vision behind lasofoxifene. The story of this program began many years before involvement at LeonaBio with the scientific conviction, persistence, and leadership of the team at Sermonix Pharmaceuticals. Dr. Portmann is a physician-scientist, entrepreneur, and the founder and CEO of Sermonix Pharmaceuticals. Over the course of his career, Dr. Portmann has served as a PI on more than 100 clinical studies and was closely involved in the phase II and phase III development of lasofoxifene. Few individuals understand estrogen receptor biology, ESR1 mutations, and the unmet needs of patients with endocrine-resistant metastatic breast cancer as deeply as David. With that, it's my pleasure to turn the call over to Dr. Portmann, who will walk you through the historical lasofoxifene clinical data to date, our phase III development strategy, and the path ahead. Following his remarks, David will lead a discussion with both Dr. Goetz and Wander on the real-world challenges clinicians face and the potential for lasofoxifene-based strategies to help address them. We'll then open the call for Q&A. Next slide, please. David, over to you. Thank you, Mark. It's a pleasure to join everyone today with our esteemed faculty to discuss the unique role lasofoxifene, a potent third-generation selective estrogen receptor modulator, plays in this dynamic and evolving space of novel endocrine therapies for the treatment of resistant ESR1-mutated breast cancer. I've been a researcher of SERMs for over two decades, these intriguing, well-tolerated tissue selective molecules have been developed in the osteoporosis, breast cancer prevention, and menopausal treatment setting. It's exciting to see lasofoxifene potentially leverage those characteristics as a combination treatment in advanced ESR1-mutated breast cancer. While lasofoxifene demonstrated an 83% reduction in new-onset primary wild-type estrogen receptor breast cancer in the osteoporosis prevention setting, our current development focus is on patients with ER-positive, HER2-negative breast cancer who have developed an ESR1 mutation. Unlike currently approved therapies that degrade the estrogen receptor, lasofoxifene modulates the receptor, providing tissue selectivity and sparing healthy estrogen receptors in critical tissues such as bone and urogenital tissue. When lasofoxifene was originally developed for the treatment of osteoporosis, its activity against emergent ESR1 mutations was unknown. These mutations commonly arise after first-line endocrine and CDK4/6 therapy. Our phase II ELAINE 2 combination trial demonstrated potential best-in-class progression-free survival, or PFS, achieving 13 months in heavily pretreated metastatic breast cancer patients, something that has not previously been seen with monotherapy but has been validated as an approach in the phase III AMEERA and EMBER-3 trials. We're currently enrolling a phase III registrational trial to test this for the lasofoxifene and abemaciclib combination. ESR1 mutations represent a major mechanism of resistance in the second-line treatment of ER-positive, HER2-negative breast cancer, the largest breast cancer population. These mutations occur in more than 40% of patients in this setting, creating a significant global market opportunity. These mutations evolve under selective pressure from aromatase inhibitor and other endocrine therapies. In response, an estrogen receptor gene mutation leads to a constitutively active ligand-independent receptor conformation, rendering current endocrine therapies inadequate and creating a clear need for novel approaches. Conventionally, the most recent approach has been to degrade or eliminate these constitutively active receptors. As a woman's health physician caring for patients for more than 20 years, I can tell you that complete estrogen receptor degradation or blockade often leads to significant tolerability and quality-of-life challenges. Our hypothesis was that lasofoxifene, a potent third-generation SERM, as a modulator, could inactivate the receptor in breast tissue without eliminating all estrogen receptor activity in other important estrogen receptor-dependent tissues. Co-crystallography provides confirmatory evidence of this. Lasofoxifene fits into the mutated receptor pocket, locking it in an antagonist conformation in breast cancer cells while retaining agonist properties in tissues like bone and vaginal tissue without evidence of endometrial hyperplasia or cancer risks like tamoxifen. This differentiates lasofoxifene from current degraders, aromatase inhibitors, and earlier-generation SERMs. An unexpected and important finding was lasofoxifene's relative potency against ESR1 mutated cell lines. As you can see in the middle figure, in vitro data shows lasofoxifene maintained potency relative to wild type ER, here seen in blue, and ESR1 mutated cell lines, in green and red, unlike fulvestrant on the left, which exhibits a significant 1-2 log drop in potency in ESR1 mutations, making it more challenging to get sufficient injectable fulvestrant on board in the presence of ESR1 mutations. Likewise, on the far right, lasofoxifene also outperformed both approved and investigational SERDs and other estrogen receptor antagonists with a four to 40-fold greater potency against mutated receptors. With such potency, this could allow effective dosing of lasofoxifene without pushing limits that can lead to toxicities such as bradycardia, GI issues, and ocular complications, none of which we've seen to date in all of our programs. ER modulators like lasofoxifene are tissue-selective, which allow these molecules to act as antagonists in some tissues, and unlike complete antagonist integrators, confer trophic benefits to important ER-containing tissues, including the vaginal epithelium. Estrogen deprivation symptoms are very common and distressing in breast cancer patients, particularly since they avoid or are fearful of traditional estrogen-containing therapies. Lasofoxifene previously demonstrated improvement in 2 phase III trials in post-menopausal vulvovaginal atrophy, and this effect was also seen here in the ELAINE 1 study in metastatic breast cancer patients with reduction on a validated PRO of vaginal dryness and painful intercourse compared to the degrader fulvestrant. We believe a treatment that potentially offers relief of these symptoms in addition to disease control would be unique among current breast cancer treatment options. Likewise, the extensive prior osteoporosis development program for lasofoxifene demonstrated improvement in bone density and reduction in fractures. The importance of anti-resorptive therapy to prevent bone metastases in breast cancer patients is well-established, and these properties of lasofoxifene might also differentiate it from SERDs and SERMs, which likely have detrimental effects on bone given their complete antagonism against the estrogen receptor. Turning now to our ELAINE programs. The newly discovered clinical activity of lasofoxifene against ESR1 mutations, with that we were granted fast-track designation by the FDA and moved quickly into a phase II program leveraging data from 40 prior phase I through III trials and characterized lasofoxifene's pharmaceutical and safety profile in depth. ELAINE 1 was a head-to-head signal-seeking study versus fulvestrant in Post-CDK4/6 aromatase inhibitor ESR1-mutated metastatic breast cancer. Dr. Goetz is the lead author of that. ELAINE 2 was an open-label study in heavily pretreated metastatic breast cancer patients with ESR1 mutations combining lasofoxifene with abemaciclib, a strategic choice given abemaciclib's broader-spectrum cyclin-inhibiting properties and Lilly's support in supplying the drug for both phase II and our ongoing global phase III registrational trial. Importantly, in 23 prior phase I studies, lasofoxifene did not demonstrate any meaningful drug-drug interactions, giving us confidence in moving into a combination setting. In ELAINE 1, results confirmed what we set out to demonstrate, that a potent modulator, as compared to a degrader, can deliver meaningful anti-tumor activity in ESR1-mutated breast cancer. This was critical to challenging the conventional thinking that these receptors must be degraded. In ELAINE 1, in patients after progression on an aromatase inhibitor and CDK4/6 inhibitor with ESR1 mutations, lasofoxifene as a monotherapy achieved a median PFS of 5.6 months, numerically superior to fulvestrant at 3.7 months, with clear separation in the Kaplan-Meier curves. As seen in other monotherapy trials like EMERALD, EMBER-3, VERITAC-2, there is a rapid drop-off after the first 2 scans, leading to the single-digit PFS of 5.6 months. While lasofoxifene monotherapy shows activity, patients deserve better. The goal for therapy should be to achieve double-digit months of PFS in the second-line setting. Importantly, lasofoxifene demonstrated excellent target engagement in ELAINE 1. On the far right, in the bottom, you can see good clearance and decrease of all ESR1 mutation variants, particularly Y537S, a notoriously difficult alteration to treat. Achieving this without degrading the receptor underscores lasofoxifene's unique advantages. Lasofoxifene's potential as an endocrine partner of choice became even more evident in ELAINE 2, where we combined lasofoxifene with abemaciclib. These patients had progressed on prior CDK4/6 inhibitors and aromatase inhibitors, most after 2 or 3 prior lines of therapy. Despite this heavily pretreated population, we observed a median PFS approaching 13 months and an objective response rate of 56%. This was unexpected and compelling, given re-challenge with CDK4/6 inhibitors after progression was still an evolving concept. This combination therapy looked like a promising strategy for these difficult-to-treat patients. Based on clinical and preclinical results, we believe the lasofoxifene and abemaciclib combination can potentially offer patients double-digit months of PFS and could offer best-in-class disease control with favorable tolerability. The central challenge in the second-line ESR1 mutation setting is achieving progression-free survival beyond 6 months median ceiling observed in both traditional and novel endocrine monotherapies and pivotal trials. This figure shows the results of ELAINE 1 and 2 on the far right. As you can see in orange, the 5.6 months achieved with Lazo compared to 3.7 months of fulvestrant is competitive with all the other SERD monotherapies approved or in development. The challenge with monotherapy in the 2L+ setting is modest efficacy as all appear unable to break past this 6-month ceiling. Fulvestrant plus abemaciclib containing 2L regimens, such as in postMONARCH, are also achieve only a modest 6 months of PFS. ELAINE 2 with 13 months PFS as well as the results from EMERALD and EMBER-3 have validated that combination approaches with novel endocrine partners can achieve promising double-digit months PFS. Given tumor heterogeneity and multiple resistance pathways in the advanced setting, combination strategy with doublet and even triplet treatment can clearly make a meaningful difference in these patients. The ELAINE 3 trial intends to confirm this approach. This all informed the currently enrolling 600-patient ELAINE 3 registrational trial of lasofoxifene and abemaciclib compared to fulvestrant and abemaciclib. This was discussed extensively with the FDA at our end of phase II meeting. The design focuses on an enriched population, all patients with an ESR1-mutated breast cancer, because all-comer designs that include wild type can potentially dilute efficacy for novel endocrine approaches compared to controls in the second-line setting. Eligible patients are pre- or post-menopausal women or men who have progressed after an aromatase inhibitor in either palbociclib or ribociclib and have an ESR1 mutation detected. This state-of-the-art design will be the largest combination 2L study in the ESR1 mutation population to date with a robust doublet comparator. This is more important than ever given that single-agent endocrine control arms are now seen as ineffective as a comparator in the advanced setting. With PFS as the primary endpoint and key secondary endpoints including overall survival, objective response rate, quality of life, patient-reported outcomes, we believe lasofoxifene's tissue selective profile can potentially offer meaningful tolerability benefits alongside strong combination efficacy and that new entrants have an opportunity to achieve commercial success in a $ multi-billion dollar category if they deliver competitive efficacy while offering superior tolerability. This is particularly important as we now have patients on these treatments for longer durations in the advanced setting. We're now more than halfway enrolled and expect top-line data readout in 2027. Working with an experienced global CRO and a team with deep expertise, we believe our timelines are achievable and that we have an opportunity to bring this promising medicine to patients expeditiously. In summary, lasofoxifene is an orally administered, well-tolerated, highly combinable therapy with compelling clinical trial results, quality of life benefits and expansion opportunities. We're excited about its best-in-class potential and thrilled to be advancing this innovative pivotal clinical development program. With that background, I'd like to now call upon our esteemed experts, Dr. Matthew Goetz from Mayo Clinic, Dr. Seth Wander from Mass General, to join me in conversation and then take questions from the audience. Matthew, Seth, really appreciate you sharing your time with us. You've been involved with the program and with novel endocrine as well as novel targeted therapies for years. Thank you so much for your time. Let me go ahead and kick this off with, you know, since we focused a lot on monotherapy versus combination therapy, perhaps let's start, Matthew Goetz, with you and, you know, how acceptable to you are the PFS and disease control that we see in SERD monotherapy trials, as well as what you are experiencing, in the real world in the clinic, and how you make decisions about who's a candidate for monotherapy versus combination in this setting? Thanks, David. I think it's important to kind of have a perspective of, you know, how did we actually get to this point? One of the reasons we got to this point was because, you know, as CDK4/6 inhibitors, you know, came into use in the first-line setting, all of a sudden, we started doing trials in the second-line setting and were shocked at the fact that endocrine sensitivity was lost in almost all patients. However, there was this group of patients that, you know, emerged, which is these patients with ESR1 mutations, where the estrogen receptor is still functional, in utilizing a drug like fulvestrant or a SERD or some other, you know, ER-targeting therapy still seem to have some benefit. I think as, you know, these studies came out, first elacestrant, then imlunestrant and others. We've seen data with giredestrant. We've seen data with camizestrant, obviously lasofoxifene. It's pretty clear that these drugs have limited anti-tumor activity. When that activity, that is by the way compared to fulvestrant, and when that anti-tumor activity is seen, it really is more in the ESR1 mutated space. Despite that, as you indicated, you know, the median progression-free survival of, let's say, somewhere between 5-6 months or 4 months is really still something that is limited. For our patients, clearly, they're looking for something, you know, that's, that's gonna be better than, you know, 3 or 4 months. I think there's a real opportunity here. First of all, these patients really do not want to go, or they're not anxious to go onto chemotherapy. We all are excited about the role of, you know, new chemotherapies with antibody drug conjugates. None of our patients are anxious to go on chemotherapy when they have a diagnosis of metastatic disease. Oftentimes with a median survival of 2, 3, or 4 years. They wanna put off chemotherapy as long as possible. Effective oral regimens, and I say oral here because that's really also very important for patients, I think is very critical. That's where I think, you know, a regimen such as lasofoxifene and abemaciclib could potentially have a large impact for our patients. Great. Seth, why don't you go ahead and maybe give us your thoughts on this issue, you know, regarding monotherapy, perhaps even monotherapy as control arms, and then also in your clinical practice. Yeah. Thanks, David and Mark, for the invitation, and great to be with you, Matthew. I agree with all the, all the great points that Matthew just made. We've certainly changed the genomic landscape of resistance and if you had had this conversation 10 years ago, the second line expectation with fulvestrant would have been substantially higher than what we see in many of the control arms today. I think in clinic right now, we're using these single agents as standard of care, either elacestrant or imlunestrant, because they're what we have. To Matthew's point, we're really not getting past that sort of four to six months, even in the ESR mutant population. The reason is because ESR1 mutation is a surrogate marker for endocrine sensitivity, but it doesn't guarantee these long, durable responses. There is important synergy in these doublet combinations. I think ELAINE 2 really hammered that point home for us. The chart that you showed looking at the 2 ceilings, right? The 6 versus the 12 months. Even with some of the newer agents, for example, imlunestrant, abemaciclib, or everolimus-based combinations with an oral SERD, they're not exceeding, for example, 12 months in the phase III setting in these randomized studies. There is an important unmet need here that I think lasofoxifene has demonstrated potential potential for. The points that Matthew brings up about wanting to stay on oral therapy and avoid chemo, and David, the points that you brought up about toxicity profile and experience on lasofoxifene are also not to be underestimated. These patients have had a lot of prior therapy. They struggle a lot with hormonal symptoms and quality of life. I think lasofoxifene is a unique drug, not just because of the long experience with lasofoxifene in the setting of bone health and vaginal health, but also because SERMs, right, are the oldest targeted therapy for estrogen-directed treatment that we have. Clinicians are comfortable with the idea of SERMs because tamoxifen has been around since the 1970s. Matthew will agree with me, our patients feel better on a SERM than they do, for example, with estrogen deprivation and on some of even some of the newer agents. I think that's an opportunity. The last point that I think you had brought up was the control arm on some of these studies. ELAINE 3 is also one of the most important studies, if not the most important study about to, you know, report out and currently accruing because you have the right control arm here. The problem with EMBER-3 was it was originally designed to be kind of a single agent comparator like EMERALD, for example. It was meant to be imlunestrant versus single agent anti-estrogen. They added the third arm, imlunestrant abemaciclib, but there's no doublet control arm. It's difficult to tease apart the relative contribution of the imlunestrant inside of that combination. One of the things that always impressed me about ELAINE 3 is that you guys were ahead of the curve. You had the right control arm built in even before we had postMONARCH data, even before we had EMBER-3 doublet data. When we finish the trial and we start to present our results, that's gonna go a long way, I think, toward convincing and providing some perspective for community practice oncologists and academic oncologists who have a little bit of a hard time interpreting, for example, the EMBER-3 data because of the nature of the clinical trial design. Those are great points. You know, your point about the historic record with tamoxifen, as a SERM, I think is very well, well-founded. Can you maybe, Matthew, speak to, you know, tolerability issues with SERMs versus SERDs? I've often heard that clinicians if patients are struggling with some symptoms on an ER, particularly sexual, and vaginal symptoms, that tamoxifen is still a very reasonable, switch. What's been your experience with maybe some of the toxicities that you see across the board with the endocrine therapies? Yeah. These are good points. You know, one of the things that I, it's a saying that I can't attribute to myself if it's one of my mentors saying who did some of the first tamoxifen studies, but I think it's true, and that is. You know, tamoxifen is a drug that saved more women's lives than any other drug in the history of all oncology. Why? You know, it's widely used and it, of course, it had just huge effects, or huge benefits, excuse me. We know that with these, the drugs that we've obviously seen, aromatase inhibitors are slightly better than tamoxifen in terms of efficacy. There's no doubt about that. We run into the issues of adherence and side effects. Then by the way, which we know that, you know, it's better for a person to be on a SERM like tamoxifen than on no therapy at all. I, we certainly know, and clinicians have great experience with the drug, tamoxifen. Lasofoxifene, of course, is a drug that's unique in the sense that it doesn't have potentially some of those adverse effects at the level of the uterus that we've seen with tamoxifen. But yet we know it's a potent inhibitor of the estrogen receptor, and this very unique observation that Donald McDonnell showed that it tightly binds ESR1 mutated receptor. I think there's been this view that you have to degrade the receptor in order to get the best efficacy for ER-targeted therapies. I think we're seeing some data suggest that that's not the case. Certainly, degradation of the receptor is important, but actually some recent data suggests that, you know, that degradation of the receptor is not always the critical aspect to ultimately, you know, inhibiting ER transcription and really the downstream effects of the estrogen receptor. All that being said, I think it's great to see a drug like lasofoxifene, a novel drug, that has clear SERM-like properties, but some of the advantages that perhaps that tamoxifen didn't have. I think we'll be really anxious to see if we can be able to begin to utilize this drug in the clinic because it's gonna fulfill a real niche. Great. Thanks for that color. You know, since it is, you know, we do think lasofoxifene has some unique properties among SERMs, particularly its potency and tissue selectivity. It is in combination with abemaciclib. I know both of you have done extensive work with abemaciclib. Can you maybe, starting with you, Seth, you know, some of the properties of abemaciclib in this second-line setting that might make it the right CDK4/6 of choice for sequencing, and how that fits in with the current landscape, given ribo and palbo's still prominence as first-line therapies along with in combination with AI. Yeah. Thanks. I think to your point, David, the work in ELAINE III is being built off of an experience that we've developed on CDK re-challenge. It's funny for me to have this conversation with Matthew because Matthew's done a lot of the pivotal original work with abemaciclib and is one of my heroes in this space. We did a lot of our work looking at resistance and on re-challenge based on some of the work that he did in the past. Rewind time a little bit back of probably 5 to 6 years ago, we were starting to develop a pretty clear picture of resistance to first-generation CDK4/6 inhibitors based on work from Matthew's team and my team and many others that suggested that there are a lot of different genomic and molecular mechanisms that can drive resistance to these drugs. At the time, whenever I would go and give a talk on this, before I had any gray hair in my beard and I was coming out of the lab and starting my practice, everybody would always ask, "What about abemaciclib after palbo?" Because at the time, palbo was the most widely utilized CDK4/6 inhibitor. We started to see the survival data with ribociclib that suggested that maybe there are some differences in terms of OS benefit in particular between these drugs. There's been a bit of a shift in the U.S. and abroad from a lot of palbociclib use in the first line to more ribociclib use. Still, everybody was interested in this idea of can you resensitize or get more mileage out of a CDK inhibitor, particularly with abema? The reason is because there are different pharmacologic and pharmacokinetic properties with abemaciclib. It's twice-daily continuous dosing. It has a different spectrum of kinase inhibition beyond 4 and 6. It has potentially better blood-brain CNS penetration. Everywhere I went, no matter where I would talk about resistance, people would ask me this question. We started to see some data from the MAINTAIN trial, which was a phase II prospective effort that our colleague Kevin Kalinsky ran, looking at ribo after palbo, showing a little bit of activity there on the order of a few months in a phase II prospective setting. We generated some retrospective multi-institutional data, single arm, looking at abema after palbo in almost 100 patients. We saw an estimated median PFS in a heterogeneous kind of academic real-world cohort of about 5-6 months. That really struck us because abema monotherapy in a CDK-naive endocrine-resistant setting from the MONARCH-1 study was about 6 months. We said, "Wow, actually, this activity looks strikingly similar to the data that we had for abema in a group of patients who never saw prior CDK." The funny thing about that is I would present that data, and I think we wrote in that paper in JNCCN that this is the best data we're ever gonna get 'cause we had approached the team to do a study like postMONARCH and it wasn't on the radar. That paper came out, MAINTAIN came out, they called me and they said, "Well, what do you think about a phase III trial of abema after palbociclib?" I said, "Great idea." Like we've you know, we really wanted to do this. That was the birth of kind of the postMONARCH study that Kevin and I did over the last few years. You showed some of the data from post-MONARCH. That was a pretty clean second-line prospective phase III trial. Everybody progressed on prior CDK. It was about 2/3, or more palbo and about, you know, a quarter to a third ribo. We saw that there was biologic activity there. The magnitude of clinical benefit was somewhat limited, but also the control arm, to Matthew's point, outperformed a little bit of what we would have expected. The fulvestrant got up to about 5 months when we really thought it was gonna be closer to 2-4 months. Despite that, it hit its statistical endpoint. To me, it proved the concept that there is at least a subset of patients where you can re-challenge, particularly with abema, for all of those pharmacologic reasons that we talked about, and there's biologic activity. The logical next step was to say, "Okay, what if we build a better anti-estrogen right into the mix?" This is where lasofoxifene comes in. David, as you know, and Matthew, you were probably a reviewer on this paper, we went back to our retrospective cohort and we started to look at the genomics, and we saw in particular that the ESR1 mutant patients had the capacity to do maybe better on an abema-based regimen in the second line setting. That was with fulvestrant, which you've already shown is really not the optimal partner. So ELAINE 3 was in many ways the kind of perfect ideological sequel to postMONARCH where we had retrospective data showing ESR1 mutant patients are getting benefit from abema re-challenge. We wanted to optimize the endocrine backbone, and we had a sense that abema of the currently available CDK4/6 inhibitors was probably the best partner candidate, to combine with the anti-estrogen. Great. That's a great perspective of how we've gotten to this point. You know, you mentioned, you know, genomic complexity and perhaps, you know, the fact that abema hits, you know, a variety of cyclins and other pathways. Matthew, maybe we can turn and dig a little bit deeper into that issue about tumor heterogeneity, polyclonal. You mentioned about the co-crystallography data that we've generated as well as pretty robust data and clearance and decrease in Y537S as well as multiple variants. Maybe you can speak to, you know, the typical genomic profiles you're seeing and how potentially combination therapy could address that tumor complexity. Yeah, this of course is, I think in many ways it's the inherent problem with the estrogen receptor. Positive breast cancer is the plasticity that we see, as well as the polyclonal. Again, it's important to note that when ESR1 is present, it's a driver. There's no doubt about it, and blocking it is critical, and we have now level one data to support that. The issue of course is that, once you block one pathway, other pathways tend to become important. I think what Seth has said is really important, and that is that there are some tumors where we are clearly seeing a signal that continuation of CDK4/6 inhibitors is actually critical. Now, it's probably not in all scenarios, but I would argue that in the presence of when the estrogen receptor continues to signal, that in that scenario, the continuation of a CDK4/6 inhibitor is important. As Seth has said, you know, one of the issues of course with palbociclib or Ibrance is, was the nature of the fact that it inhibited 4/6, but it was a lot of off-on, off-on that really didn't fully, you know, suppress proliferation and really that RB pathway that led to, you know, some of the observations that we saw is that when you sort of stop the CDK4/6 inhibitor, you ended up seeing in some cases marked clinical progression. That was not all the cases because that's of course the problem is that resistance, there's a lot of heterogeneity. I think it's very clear from the postMONARCH data that dual targeting of both CDK4 as well as ER is critically important. That utilizing abemaciclib as a means to better target CDK4 with, you know, instead of the off-on, but continuous targeting of CDK4. As well as the fact we know that that drug has as Seth has already said, inhibits other kinases. You know, the older we get, the more we realize that sometimes drugs that inhibit more than one pathway sometimes are more effective. That may be one of the reasons that, you know, abemaciclib has shown really potent anti-tumor activity and probably in some of these most difficult to treat cases. If I go back to our, an analysis that we did years ago of MONARCH 2 and 3, one of the things we showed was that the, where the drug really shown or if you will, demonstrated real value was in these very difficult to treat scenarios. Patients with very short, if you will, treatment-free intervals. You know, patients who progressed fairly quickly, patients who had visceral disease such as hepatic disease, high-grade disease, low PR. These are the more difficult cases to treat and of course that ESR1 mutations is definitely within that scope. Again, this is, I think one also additional advantage of this combination. Great. I could certainly go on with the both of you and your expertise, but I think we probably should go ahead and open it up to our attendees. I am sure they are anxious to ask our experts some questions. If I can turn it over now to the operator and have her triage some calls for you. Yeah. Thank you. We will now begin the question and answer session. To ask a question, please raise your hand by clicking the Raise Hand button on the bottom of your screen and wait for your name to be called. Just one moment as we compile the queue. If there's, if there's nobody yet in the queue, I don't know if Mark has anything he'd like to ask our experts while we're waiting. Yeah. I mean, one of the questions that we sort of wrestle with is really on the sort of toxicity side. Again, the more the field goes towards doublet and triplet, efficacy and getting better efficacy, there's always this wrestle with toxicity. Maybe it would be interesting to get your take on, as you do doublets and triplets, what are the things that you get concerned about and what really causes patients to not be able to do those type of therapies? Yeah. I can, I can start. I think, Mark, this a really important point, and I'm sure Matthew would agree with me that even just 5-plus years ago if you had said we were gonna be doing triplets, right, in the first or second line ER-positive metastatic, we would have thought that that was a little bit crazy. The therapeutic index for many of the targeted therapies in particular, PI3K pathway inhibitors, even CDK inhibitors are not insignificant. I think they're not as bad as chemotherapy, but they're there. Some of the newer drugs, and lasofoxifene is a great example of this, allows a better therapeutic window so that you have more combinability. I think it is underappreciated that not all of the next generation antiestrogens are equally tolerable. There are some unique toxicities to some of these drugs. Bradycardia, photopsia, some at least moderate, GI, you know, rates of toxicity, cytopenia in some cases with some of the newer drugs that would potentially impact the ability to go into doublet and triplet regimens moving forward. For a doublet regimen to move into the first and second line, and even in the adjuvant, right, setting for longer durations, it has to have a better therapeutic window, better tolerability. I think we see that with lasofoxifene. I think abema is a great partner, at least in the current landscape, we'll have future opportunities to build upon this regimen with even better new combinations that have even better therapeutic windows. I think this is the next step from ELAINE 1 and ELAINE 2, the combinability of the drug is very good, in my opinion. Great. operator, do we have? You have. Yep. We do have a question from Daniel Bronder from Cantor Fitzgerald. Daniel, please unmute your microphone. You may proceed. Hey. Good afternoon. It's Daniel Bronder on for Eric Schmidt. We have a question for the authors of the ELAINE 3 trial design paper. We noticed that there is some language that pertains to a non-binding futility interim analysis, and we were just wondering what would determine whether you go ahead with this analysis and if the company was planning to make an announcement if or when that happens. I think I'll let Mark maybe take that first. I believe that it is contemplated that there will be a futility analysis on the data. We're still working through what the specifics will be that, but it will not be based on efficacy. Thank you. Our next question comes from Douglas MacPherson from Mizuho. Douglas, you may unmute your mic and proceed. Hi there. Nice to see everyone. Thanks for taking my question. I have two quick ones, the first one is kind of a two-parter. For ESR1 mutations, are there, like, degrees of expression of ESR1 and/or co-mutations that in which patients might be expected to, like, respond better or worse to lasofoxifene? The second part of that question is, how routine is ESR1 screening? Is it something that's just sort of done par for the course every time or is it something for which physicians still need a degree of education and sort of the testing's evolving? I could maybe take the latter question. I would say that, you know, once elacestrant came out, you know, this was really, if you will, the first, you know. The, I think in academic, right, call us in ivory towers, we're doing this all the time. The question is, what are the people doing out in the community? I think out in the community, you know, once we had a drug that was FDA-approved for that specific alteration, it really led to, you know, the revolution of getting sequencing done out in the community. Of course, what we've gone from, you know, just maybe one company available now to multiple companies that are available, Guardant, Caris, you know, Foundation Medicine. There's others as well. We now have really, I think, you know, you know. The ELAINE study is coming at the right time because these drugs are already out there. Obviously they have limited antitumor activity, but sequencing is really standard of care because we've got FDA-approved drugs. We don't just test for ESR1. We do broad testing because there are other drug targets, such as drugs that target the PI3K/AKT pathway, and we expect others in the future as well. I think, I think we're nicely set up, if you will, for when the ELAINE 3 results come out. Maybe Dr. Wander can take that first part of the question about, you know, the degree to which either mutant allele fraction, polyclonality, I know that's a topic that's near and dear to him, might impact treatment selection. Yeah, very interesting question. I'm very curious to hear what Matthew thinks of my answer and we'll get his thoughts on it too in a second. We're still learning a lot about this, right? The mutational profiles within and beyond ESR1 and how those are engaged by these newer agents. One of the things I love the most about, in particular, the ELAINE 1 paper, and I wrote this in an accompanying editorial 'cause at the time, I wasn't involved in the study at that time so I could be an outside kind of commentator on it, was the data that your team generated, in my opinion, was far beyond anything that had been generated from any of the concurrent next generation anti-estrogens. You showed a piece of it, David, looking at breaking down the ESR1 by allelotype. People have a misconception that all ESR1 mutations are the same, and that's not true. It's not surprising when you think about it that some mutations have different neomorphic activities or what we might call different kind of virulence. Some can do okay with fulvestrant, some really can't, right? The Y537, as you mentioned, in particular, is sort of a very bad player, and we've seen that in laboratory models and in other clinical data sets. One of the most impressive things about ELAINE 1 is regardless of the type of ESR1 mutation, you're seeing deep reductions in allelic fraction on lasofoxifene. When you look in particular at the Y537S, the average patient on fulvestrant has about an 80% increase in the amount of allelic fraction, whereas the average person on lasofoxifene has an 80%-90% decrease in ESR1. That is very striking because the bar plot was going in the exact opposite direction. Now the other part of that question is what about concurrent mutations with ESR1? I think we have some at least indirect evidence that there certainly are other mutations that would impact not so much ESR1, but the degree of endocrine sensitivity. How do we know that? We know because when you enrich for the ESR1 mutant population, yes, they do better on elacestrant, imlunestrant, lasofoxifene, et cetera, but there's still a drop. There's still a pretty steep drop in the curve right at the beginning, which suggests that there's some other factor, and we can hypothesize, Matthew and I would probably agree, it's RAS, it's FGFR, it's other genes that have been implicated in endocrine independence. You could still resensitize if you had the right partner there. Thinking about future development plans for those patients who we are calling right now endocrine resistant, where you have a good anti-estrogen like lasofoxifene and you know the target, the thing that's overcoming the ESR1, like a RAS inhibitor or a MEK inhibitor or an FGFR inhibitor, I think to me is a very attractive strategy. I think we're still looking at data from the ELAINE trials, looking at data in the real world academic setting on elacestrant and imlunestrant to tease apart the higher level of complexity, ESR1 plus X. We are definitely going to get there, and we're going to get there by looking at dynamic sequencing over time in non-responders and also in patients who develop resistance after some period. Matthew, I don't know if you have other thoughts on that. No, I think it's well said. You know, the reality is that not all these ESR1 mutations are created equal, as you said. If you have two different drugs and one, you know, is able to target the nastiest mutation, the rest of them are fine, right? If you have one that can only target one or two, then you're in trouble. I think that's really the advantage here of lasofoxifene is it has that ability to target what we think is some of the worst acting mutations. Clearly we can see polyclonal, and that's one of the problems that we see. Again, another advantage for the drug. I would just say, let me add one point. Thank you for reminding me, Matthew. David, you brought up the polyclonal. This is also an area where we haven't had a lot of deep investigation, so our team generated some preliminary data on elacestrant monotherapy that higher degrees of polyclonal, more than 4 or more variants within the individual patient, seem to maybe be doing worse on some of the next generation oral SERDs. I would like to see how lasofoxifene with abema fares even in that setting. Yeah Worst of the worst ESR1 mutant patients. I hope and suspect that that combo will still potentially be quite effective where we're starting to see the next generation monotherapy falling off. Those are great points. We presented some data at San Antonio from ELAINE 2 that when there were co-alterations, different resistance mechanisms that we still saw significant activity largely due to addressing it by multiple pathways with a combination. We'll have a really rich data set from ELAINE 3 with so many patients and genomic profiling on everyone. Operator, do we have another question? We do. Our next question comes from Tom Shrader from BTIG. Tom, please unmute and you may proceed. Hey, you hear me okay? Yeah. Thank you for the overview. It's such a complicated space. It's, it's a wonderful overview. A quick one for the company or maybe the KOLs. I think one of the nice things about abema is it gets into the CNS. Does lasofoxifene is it gonna follow it, and does it matter for a second-line drug to you? Would that be? It might be a clear reason to use the drug. Kind of a broad one for the KOLs. You presumably see everything that's coming. I'm sure you're in 1 million clinical trials. Do you expect second line to stay, CDK re-challenge and even a better hormonal therapy, or is there stuff coming that would be tolerable but maybe better? Thanks for the thoughts. I'll go ahead and let, you know, maybe, Matthew, if you wanna take a first crack at that. Yeah, I mean, you know, it may seem complicated. At the same time, I think it's relatively simple. That is patients are gonna continue to be treated with oral therapy in the first-line setting. There's gonna be a group of patients that develop ESR1 mutations. Our goal is gonna be how best to treat those patients. The third thing is chemotherapy is not a great option. That is, it works. Patients really don't want it right away. They wanna preserve quality of life. I think from that standpoint, we're gonna continue to need to have drugs that target ESR1. It's gonna continue to be an issue. As Seth said, you know, it's gonna come down to what's the best, you know, combination because it is a worst acting group, and we're really not gonna be using a lot of monotherapy in this setting. I think there are some exceptions, of course. You know, there are some rare exceptions. With regard to the brain metastases, you know, we rarely see brain metastases in the second-line setting. Do we see it? Yes, we do in ER-positive. It's oftentimes more in that later lines. Although, you know, theoretically the abemaciclib has that advantage, that's not always the immediate issue that we're dealing with. I would say it's probably less than 5% of patients that we see brain metastases come up as a major problem in the 2L setting. Again, I think it's that theoretical advantage for abemaciclib. Certainly, Seth, you can comment from post-MONARCH in terms of the number of patients that develop brain metastases in that study, but I can't recall that in that phase III trial that that was really a major problem. Yeah. Thanks, Matthew. I have to go back, I don't want to cite the data wrong. I don't recall it being a high proportion, and I agree with you. We expect it later. To your point, you may reduce seeding, you know, successful seeding to the CNS by earlier integration of CNS active agents. I agree with this idea of iterating and combining with better tolerated targeted agents. The other thing I would say about the current landscape, the question that you just asked, Matthew, I'm curious your thoughts on this as well. To me, just taking a step back and looking kind of 50,000 feet, we do have a lot of next generation antiestrogens in the mix, some of which have single agent approvals, some of which have doublet, phase III data. My summary of this is that you have all these oral SERDs fighting with each other. There are many of them. Some of the drugs are sort of floating above the fray. You can imagine like a boxing match where you have the under fight, and then you have kind of like the over fight. You know, the, the heavyweight fight. I think people are paying attention to the details between the SERDs, but they really are in many ways interchangeable with some to-slight toxicity differences. giredestrant, camizestrant, elacestrant, imlunestrant. The trials are designed differently, SERENA-6 versus EMBER-3 versus EMERALD. You had the PROTAC, which everybody was sort of paying a lot of attention to, but that was on the upper level, and it almost got knocked down because, again, we didn't really see any activity in the ITT. To me, looking across this landscape, I view lasofoxifene as sort of operating potentially on a different level than these oral SERDs in the PROTAC. We're paying attention to the CERAN, right? Which also is a distinct mechanism. You know, David, you can comment on this also. It's my opinion, and you know this and others know this. I think lasofoxifene may also have a future in the ESR1 wild type population. We have data for that, and it makes good sense based on what we know about tamoxifen and SERMs in general. So you have the SERDs fighting down here, but we're actually looking at some of these newer mechanisms and drugs as floating above that could really reshape the way we think about the field and combinability and future doublet and future triplet regimens beyond just Abema. Yeah. No, those are great points. Tom, to your first part of the question, we do have broad penetration in all tissues. While brain mets are rare in this setting, we could get there if needed. Regarding wild type, we definitely you know assume given lasofoxifene's similar potency against wild type in vitro and in vivo, being able to prevent breast cancer in osteoporotic patients, even the higher risk by Gail model, which would all be wild type by 83% with only a half a milligram of lasofoxifene, let alone 5 milligrams, certainly shows some activity against wild type. We were an arm of the I-SPY 2 endocrine optimization protocol where we saw really good suppression of Ki-67 in primary breast cancer, which was all wild type. I think all good points. Operator, anybody else in the queue? We have a question from Josh Bowen from Guggenheim. Josh, please unmute. You may proceed. Might still be muted. Josh? Well, while we wait, I'll wait a moment for that. We do have another question from Douglas MacPherson. Douglas, you may unmute and ask your question. Hi again, thank you for taking my second question, which is also a two-parter, if I may. The first part is for ELAINE III. Are there any notable differences in the patient populations between ELAINE II and ELAINE III? The second part of that is. For ELAINE III, the timeline for completion of enrollment and expected top-line data are, like, pretty tight if we're expecting a 13-month PFS. I imagine it's, like, event-triggered, a number of events you're expecting. Sort of any color on what's gonna trigger the top-line data analysis? I'll try to maybe unpack that and then let both Mark and our experts chime in. ELAINE 2 was a much more heavily pre-treated population than ELAINE 3. For instance, half of the patients in ELAINE 2 had received chemotherapy in the metastatic setting. 80% had received prior fulvestrant along with an AI CDK. Several had several lines of CDKs and other targeted therapies. Whereas you're looking at largely on average a third or fourth line population in ELAINE 2, ELAINE 3 is going to be mostly second line with some chemo. As our doctors would tell you, the chemo's usually relegated to much later in their treatment journey. We're not anticipating a lot of chemo. Almost a pure second line population. Mark maybe can guide, on, you know, on data readouts and enrollment. Sure. Enrollment is going very well. We continue to push. You know, we're guiding towards back end of this year to get completion of enrollment. We've just estimated 12 months just to share, 'cause we really don't know. That would be back end of 2027. That's as much as the crystal ball that I know. You're right. It's event-driven. You know, Bicar event-driven, so, you know, that, you know, we'll have to let the game play out. I can understand that. Thanks so much. David, maybe one, you know, I'd like Seth's input on this as well. You know, in the 2L setting, for patients who progress on a CDK4/6 inhibitor, you know, whether we are using, let's say, fulvestrant plus a PI3K inhibitor, or we're using a CDK4/6 inhibitor, combination or, you know, single agent. You know, one of the things that we typically see is, you know, median PFSs as Seth said. You know, patients really say, "What the heck is a PFS," right? What they can relate to is whether the tumor shrinks. One of the things that was remarkable in ELAINE 2 is even that we had a relatively small population of patients that were evaluable. I was just looking back at the data. It's about 18 patients in that study that were evaluable for response, meaning liver disease, et cetera. The response rate was pretty remarkable. It was 55%. Patients can relate to that. That is, my tumor is actually shrinking. Again, I think that's another thing, maybe that speaks a little bit to that synergistic aspects of these two drugs together that Seth was talking about before. Yeah. I agree, man. That's a, that's quite a high marker, for this type of, you know, line of therapy and endocrine-based treatment. Certainly endocrine monotherapy and even some of the other doublets, that we've been talking about, like for example, Everolimus-based doublets, I don't think you're seeing response rates, you know, getting up into the 60-ish%. You know, you would say probably if we were meeting with a company designing a trial and you're hitting response rates in the 20-30% and a median PFS above 6 months, you're saying, "Okay, like, let's, you know, let's go." That would be far in excess of those benchmarks. Great. Thank you for that. Operator? That wraps up our Q&A. Okay. Well, you know, this has been incredibly informative. We really appreciate your time and expertise. I think we've covered a lot of ground. Obviously, there's still a lot more to discuss. Let me go ahead and turn it over to Mark to close us out. Thanks, David. Wow, what a great discussion. I'd just like to take a moment to reflect on what we heard and why we believe this conversation matters. Over the last hour, we've heard from clinicians who are not only treating patients on the front line, but are also shaping this field and how we think about resistance, modulation, sequencing, combination therapies, and really the future of endocrine therapy. What came through very clearly is while there's progress in the ER-positive metastatic breast cancer, there's been meaningful work done, but there still needs to be more work done. Particularly, you know, we're just understanding the mutations, the genotype, and how, you know, how important it is to have novel therapies in this space. What today's discussion reinforces a fundamental shift in how leaders in the field are approaching this challenge. The question is no longer whether endocrine therapy remains relevant, but rather how we can do it better. Better receptor biology, better precision medicine, better durability, better combinations, and critically better quality of life for patients who remain on therapy for years. As you heard loud and clear, we believe lasofoxifene sits squarely in the center of this evolution. As discussed today, lasofoxifene and its differentiating mechanism as a potent estrogen receptor modulator rather than a degrader creates the opportunity to rethink what an endocrine backbone can and should be. One that is active against ESR1 mutations, one that is highly compatible with combination strategies, and one that has the potential to deliver not just efficacy, but tolerability that matters for patients living with metastatic disease. Importantly, this is not a theoretical proposition. The clinical, translational, and real-world perspectives shared today underscore why modulating the estrogen receptor thoughtfully and precisely may ultimately prove foundational as the standard of care continues to evolve. For us at LeonaBio, this is why lasofoxifene is far more than a late-stage asset. It is a program that reflects our strategy and our conviction to invest where science, unmet need, and clinical insight converge, and to advance therapies that have the potential to change the trajectory of serious diseases. I also wanna take a moment to thank our panelists and moderator. The depth, candor, and rigor you brought today's discussion are exactly what we hoped for when we set out to host this event. We're grateful for your leadership, your partnership, and most importantly, your continued commitment to improving outcomes for patients. To everyone who joined us today, investor, clinicians, and members of the broader community, thank you as well for your time and engagement. We hope today's discussion was as informative and thought-provoking for you as it was for us. We are energized by the path ahead, confident in the science, and deeply motivated by the patients we aim to serve. We look forward to continuing this dialogue as the data emerge, and we look forward to the goal of bringing a differentiated, meaningful new option to those who need it most. Thank you again for joining us, and have a great rest of the day.