LeonaBio, Inc. ($LONA)

Good afternoon, and thank you for joining LeonaBio's key opinion leader call. [Operator Instructions] A replay of today's event will be available on the Investors section of the LeonaBio website. I would now like to turn the call over to Mark Litton, President and CEO of LeonaBio.

Thank you, Elissa, and 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 2 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 Investors section of the LeonaBio website for more information concerning the risk factors that could affect the company. In addition, 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 decision 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. And 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. second-line breast cancer segment alone exceeding $5-plus billion annually. A substantial portion of these patients harbor ESR1 mutations. And 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 2 outstanding physician scientists. Dr. Matthew Goetz, who's 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 offered 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 Mass 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 offered more than 70 peer-reviewed publications in precision oncology. Moderating today's discussion is David, Dr. Portman, 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. Dr. Portman is a physician scientist, entrepreneur and the Founder and CEO of Sermonix Pharmaceuticals. Over the course of his career, Dr. Portman 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. Portman, 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 of 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 2 decades, and these intriguing well-tolerated tissue selective molecules have been developed in the osteoporosis, breast cancer prevention and menopausal treatment setting, and 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 evERA 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, and 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 confirmation, 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. But as a women'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 and other important estrogen receptor-dependent tissues. Cocrystallography provides confirmatory evidence of this. Lasofoxifene fits into the mutated receptor pocket, blocking it in an antagonist confirmation 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 in ESR1 mutated cell lines, in green and red, unlike fulvestrant on the left, which exhibits a significant 1 to 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 4 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 and degraders 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 postmenopausal vaginal 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 antiresorptive 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 characterize 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 antitumor 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 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. And 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 evident -- 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 rechallenge with CDK4/6 inhibitors after progression was still an evolving concept, but 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 in 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 laso 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 abemaciclib containing 2L regimens, such as in post MONARCH are also achieved only a modest 6 months of PFS. ELAINE-2 with 13 months PFS as well as the results from evERA 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. And 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 postmenopausal 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 multibillion-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 time lines are achievable and that we have an opportunity to bring this promising medicine to patients expeditiously. So 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. So 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. So Matt, 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. And thank you so much for your time. Let me go ahead and kick this off with -- since we focused a lot on monotherapy versus combination therapy, I'd love to perhaps let's start, Matt, with you and how acceptable to you is -- 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 how did we actually get to this point. And one of the reasons we got to this point was because as CDK4/6 inhibitors 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 really quite was lost in almost all patients. However, there was this group of patients that emerged, which is these patients with ESR1 mutations, where the estrogen receptor is still functional and utilizing a drug like fulvestrant or a SERD or some other ER-targeting therapy still seem to have some benefit. But I think as these studies came out first, elacestrant and 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 antitumor activity. And when that activity -- that is, by the way, compared to fulvestrant and when that antitumor activity is seen, it really is more in the ESR1 mutated space. And so despite that, as you indicated, the median progression-free survival of, let's say, somewhere between 5 to 6 months or 4 months is really still something that is limited. And for our patients, clearly, they're looking for something that's going to be better than 3 or 4 months. So 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 on to chemotherapy. We all are excited about the role of new chemotherapies with antibody drug conjugates. But none of our patients are anxious to go on chemotherapy when they have a diagnosis of metastatic disease, who oftentimes with a median survival of 2, 3 or 4 years, they're really -- they want to put off chemotherapy as long as possible. So effective oral regimens, and I say oral here because that's really also very important for patients, I think is very critical. And so that's where I think 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 regarding monotherapy, perhaps even monotherapy as control arms and then also in your clinical practice.

Yes. Thanks, David and Mark, for the invitation. Great to be with you, Matt. I agree with all the great points that Matt just made. We've certainly changed the genomic landscape of resistance. And if you 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. But to Matt's point, we're really not getting past that sort of 4 to 6 months even in the ESR mutant population. And the reason is because ESR1 mutation is a surrogate marker for endocrine sensitivity, but it doesn't guarantee these long durable responses. And there is important synergy in these doublet combinations. And 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, abema 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. So there is an important unmet need here that I think lasofoxifene has demonstrated potential for. The points that Matt 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. And I think lasofoxifene is a unique drug, not just because of the long experience of 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. And Matt will agree with me, our patients feel better on a SERM than they do, for example, with estrogen deprivation and on even some of the newer agents. And so 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. So ELAINE-3 is also one of the most important studies, if not the most important study about to report out and currently accruing because you have the right control arm here. So 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 abema, but there's no doublet control arm. So it's difficult to tease apart the relative contribution of the imlunestrant inside of that combination. And 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 post MONARCH data, even before we had EMBER-3 doublet data. And when we finish the trial and we start to present our results, that's going to 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. Your point about the historic record with tamoxifen as a SERM I think, is very well founded. Can you maybe, Matt, speak to tolerability issues with SERMs versus SERDs? I've often heard that clinicians if patients are struggling with some symptoms on an AR, particularly sexual and vaginal symptoms that tamoxifen is still a very reasonable switch. So what's been your experience with maybe some of the toxicities that you see across the board with the endocrine therapies?

Yes, these are good points. And 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 tamoxifen is a drug that saved more women's lives than any other drug in the history of all oncology. Why? Because it's widely used and of course, it had just huge, huge effects or huge benefits, excuse me. And we know that with these drugs that we've obviously seen aromatase inhibitors are slightly better than tamoxifen in terms of efficacy. There's no doubt about that. But we run into the issues of adherence and side effects. And then, by the way, which we know that it's better for a person to be on a SERM like tamoxifen than on no therapy at all. So 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 in this very unique observation that Donald McDonnell showed that it tightly binds ESR1 mutated receptor. And so I think there has been this view that you have to degrade the receptor in order to get the best efficacy for ER-targeted therapies. And 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 degradation of the receptor is not always the critical aspect to ultimately inhibiting ER transcription and really the downstream effects of the estrogen receptor. So 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 the tamoxifen didn't have. And 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 going to fulfill a real niche.

Great. Thanks for that color. Since it is -- we do think lasofoxifene has some unique properties among SERMs, particularly its potency and tissue selectivity. But it is in combination with abemaciclib. So I know both of you have done extensive work with abema. Can you -- maybe starting with you, Seth, 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 still prominence as first-line therapies along with -- in combination with AI?

Yes, thanks. I think to your point, David, the work in ELAINE-3 is being built off of an experience that we've developed on CDK rechallenge. And it's funny for me to have this conversation with Matt because Matt's done a lot of the pivotal original work with abeam, and he is one of my heroes in this space. And we did a lot of our work looking at resistance and on rechallenge based on some of the work that he did in the past. So rewind time a little bit back 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 Matt'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. And 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 abema after palbo, because at the time, palbo was the most widely utilized CDK4/6 inhibitor. And then 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. So there's been a bit of a shift in the U.S. and abroad from a lot of palbo use in the first line to more ribo use. But still, everybody was interested in this idea of can you resensitize or get more mileage out of a CDK inhibitor, particularly with abema. And 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. And so everywhere I went, no matter where I would talk about resistance, people would ask me this question. And we started to see some data from the MANTAIN 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. And then we generated some retrospective multi-institutional data, single arm, looking at abema after palbo in almost 100 patients. And we saw an estimated median PFS in a heterogeneous kind of academic real-world cohort of about 5 to 6 months. And that really struck us because abema monotherapy in a CDK-naive endocrine-resistant setting from the MONARCH 1 study was about 6 months. So 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. And 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 going to get because we had approached the team to do a study like post MONARCH, and it wasn't on the radar. That paper came out, MAINTAIN came out, and then they called me and they said, well, what do you think about a Phase III trial of abema after palbo? I said, great idea. Like we really wanted to do this. So that was the birth of kind of the post-MONARCH study that Kevin and I did over the last few years. And we showed some of the data from post MONARCH. So 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 1/4 to 1/3 ribo. And we saw that there was biologic activity there. The magnitude of clinical benefit was somewhat limited, but also the control arm, to Matt'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 going to be closer to 2 to 4 months. Despite that, it hit its statistical endpoint. And to me, it proved the concept that there is at least a subset of patients where you can rechallenge, particularly with abema for all of those pharmacologic reasons that we talked about, and there's biologic activity. And so the logical next step was to say, okay, what if we build a better antiestrogen, right, into the mix. And this is where lasofoxifene comes in. And David, as you know, and Matt, 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. And that was with fulvestrant, which you've already shown is really not the optimal partner. And so ELAINE-3 was, in many ways, the kind of perfect ideological sequel to post MONARCH, where we had retrospective data showing ESR1 mutant patients are getting benefit from abema rechallenge. We wanted to optimize the endocrine backbone, and we had a sense that abema of the currently available 4/6 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 mentioned genomic complexity and perhaps the fact that abema hits a variety of cyclins and other pathways. Matt, maybe we can turn and dig a little bit deeper into that issue about tumor heterogeneity, polyclonality. You mentioned about the cocrystallography 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 the typical genomic profiles you're seeing and how potentially combination therapy could address that tumor complexity.

Yes. 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 polyclonality. And 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 1 data to support that. The issue, of course, is that once you block one pathway, other pathways tend to become important. And 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. And as Seth has said, one of the issues, of course, with palbociclib IBRANCE is 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 suppress proliferation and really that RB pathway that led to 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. And that was not all the cases because that's, of course, the problem is that resistance, there's a lot of heterogeneity. But I think it's very clear from the post-MONARCH 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 -- 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. And the older we get, the more we realize that sometimes drugs that inhibit more than one pathway sometimes are more effective. And that may be one of the reasons that abemaciclib has shown really potent antitumor activity and probably in some of these most difficult-to-treat cases. If I go back to an analysis that we did years ago of MONARCH 2 and 3, one of the things we showed was that 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. So patients who progress fairly quickly, patients who had visceral disease, such as hepatic disease, high-grade disease, low PR. So these are the more difficult cases to treat. And of course, that ESR1 mutations is definitely within that scope. And so again, this is, I think, one also additional advantage of this combination.

Great. So I can certainly go on with both of you and your expertise, but I think we probably should go ahead and open it up to our attendees. I'm sure they are anxious to ask our experts some questions. So if I can turn it over now to the operator and have her triage some calls for you.

[Operator Instructions].

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.

Yes, I mean one of the questions that we sort of wrestle with is really on the sort of toxicity side. And what is -- again, the more the field goes towards doublet and triplet efficacy and getting better efficacy, there's always this wrestle with toxicity. So maybe it would be interesting to get your take on, as you do, 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?

Yes, I can start. I think, Mark, that's a really important point, and I'm sure Matt would agree with me that even just 5-plus years ago, if you had said we were going to be doing triplets, right, in the first or second-line ER-positive metastatic, we would have thought that, that was a little bit crazy because 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. And some of the newer drugs, and lasofoxifene is a great example of this, allows a better therapeutic window so that you have more combinability. And I think it is underappreciated that not all of the next-generation anti-estrogens are equally tolerable. There are some unique toxicities to some of these drugs. Bradycardia, Photopsia, some at least moderate GI 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. And so 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, but we'll have future opportunities to build upon this regimen with even better new combinations that have even better therapeutic windows. So I think this is the next step from ELAINE-1 and ELAINE-2, but the combinability of the drug is very good, in my opinion.

Yes. We do have a question from Daniel Bronder from Cantor.

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 nonbinding 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'll let Mark maybe take that first.

Yes. 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.

Our next question comes from Douglas Macpherson from Mizuho.

I have 2 quick ones, and the first one is kind of a 2-parter. For ESR1 mutations, are there like degrees of expression of ESR1 and/or co-mutations in which patients might be expected to like respond better or worse lasofoxifene? And 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 is evolving?

I can maybe take the latter question. I would say that once elacestrant came out, this was really, if you will, the first -- I think in academic, right, call it an ivory towers, we're doing this all the time. The question is what are the people doing out in the community. And I think on the community, once we had a drug that was FDA approved for that specific alteration, it really led to the revolution of getting sequencing done out in the community. And of course, we've gone from just maybe one company available now to multiple companies that are available Guardant, Caris, Foundation Medicine, there's others as well. And so we now have really -- I think 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. And we don't just test for ESR1. We do broad testing because there are other drug targets ,such as targets that are drugs that target the PI3 kinase AKT pathway, and we expect others in the future as well. So 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 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.

Yes, very interesting question. I'm very curious to hear what Matt thinks of my answer, and we'll get his thoughts on that 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 because 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. And you showed a piece of it, David, looking at breaking down the ESR1 by allele type. So 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 variances. Some can do okay with fulvestrant, some really can't, right? And 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, deep reductions in allelic fraction on lasofoxifene. And when you look in particular at the Y537S, the average patients on fulvestrant has about an 80% increase in the amount of allelic fraction, whereas the average person on lasofoxifene has an 80% to 90% decrease in ESR1. And that is very striking because the curves -- the bar plot was going in the exact opposite direction. Now the other part of that question is, what about concurrent mutations with ESR1? And 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. And 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 Matt and I would probably agree, it's RAS, it's FGFR, it's other genes that have been implicated in endocrine independence. Now you could still resensitize if you had the right partner there. So 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 MEK inhibitor or an FGFR inhibitor, I think to me is a very attractive strategy. And 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, but we are definitely going to get there. And we're going to get there by looking at dynamic sequencing over time in nonresponders and also in patients who develop resistance after some period. Matt, I don't know if you have other thoughts on that.

No, I think it's well said. And the reality is that not all the ESR1 mutations are created equal, as you said. And if you have 2 different drugs and one is able to target the RAS mutation, the rest of them are fine, right? But if you have one that can only target 1 or 2, then you're in trouble. So 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. And clearly, we can see polyclonality, and that's one of the problems that we see. And so again, another advantage for the drug.

And I would just say, only add one point, thank you for reminding me, Matt and David, you brought up the polyclonality. 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 polyclonality, more than 4 or more variants within the individual patients 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. So these are the 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. So we presented some data at San Antonio from ELAINE-2 that when there are coalterations, different resistance mechanisms that we still saw significant activity, largely due to addressing it by multiple pathways with a combination. And 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.

Thank you for the overview. It's such a complicated space. 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 laso is it going to follow it? And does it matter for a second-line drug to you? Would that be -- might be a clear reason to use the drug? And then 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 rechallenge and even a better hormonal therapy? Or is there stuff coming that would be tolerable but maybe better?

I'll go ahead and let maybe, Matt, if you want to take a first crack at that.

Yes, I mean, it may seem complicated, but at the same time, I think it's relatively simple. And that is patients are going to be -- continue to be treated with dual therapy in the first-line setting, and there's going to be a group of patients that develop ESR1 mutations. And our goal is going to be how best to treat those patients. And the third thing is chemotherapy is not a great option. That is it is works but patients really don't want it right away, they want to preserve quality of life. So I think from that standpoint, we're going to continue to need to have drugs that target ESR1. It's going to continue to be an issue. And as Seth said, it's going to come down to what's the best combination because it is a worse-acting group and we're really not going to be using a lot of monotherapy in this setting. I think there are some exceptions, of course. There are some rare exceptions. And then with regard to the brain metastases, 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 line. And so, although, theoretically, abemaciclib has that advantage, that's not always the immediate issue that we're dealing with. And I would say it's probably less than 5% of patients that we see brain metastases come up as a major problem in the second-line setting. Again, I think it's a theoretical advantage for abemaciclib. But 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.

Yes. Thanks, Matt. I have to go back, and 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. And to your point, you may reduce seeding, successful seeding to the CNS by earlier integration of CNS active agents. And 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, and Matt, 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 anti-estrogens 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, and there are many of them. But some of the drugs are sort of floating above the fray. And you can imagine like a boxing match where you have the under-fight and then you have kind of like the over-fight, 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 slight toxicity differences, giredestrant, camizestrant, elacestrant, imlunestrant. The trials are designed differently, SERENA-6 versus EMBER-3 versus EMERALD. Then you have the PROTAC, which everybody was sort of paying a lot of attention to. But that was on the upper level and then it almost got knocked down because, again, we didn't really see any activity in the ITT. And so to me, looking across this landscape, I view lasofoxifene as sort of operating potentially on a different level than these oral SERDs and the PROTAC. We're paying attention to the SERM, right, which also is a distinct mechanism. But 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. And so you have the SERDs fighting down here, but we're actually looking at some of these newer mechanisms and drugs that's floating above that could really reshape the way we think about the field and combinability and future doublet and future triplet regimens beyond just the abema.

Yes. No, those are great points. And Tom, to your first part of the question, we do have broad penetration in all tissues. So while brain mets are rare in this setting, we could get there if needed. And then regarding wild-type, we definitely assume given laso'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 0.5 milligram of lasofoxifene, let alone 5 milligrams certainly shows some activity against wild type. And then 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. So I think all good points. Operator, anybody else in the queue?

We have a question from Josh Bowen from Guggenheim. Josh? Well, while we wait, I'll wait a moment for that. We do have another question from Douglas Macpherson.

My second question, which is also a 2-parter, if I may. The first part is for ELAINE-3, are there any notable differences in the patient populations between ELAINE-2 and ELAINE-3? And then the second part of that is, for ELLANE-3, the timeline for completion of enrollment and expected top line data are like pretty tight if we're expecting a 13-month PFS. Are there -- I imagine it's like event triggered number of events you're expecting, sort of any color on what's going to trigger the top line data analysis?

Yes, I'll try to maybe unpack that and then let both Mark and our experts chime in. So ELAINE-2 was a much more heavily pretreated population than ELAINE-3. So 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. So 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. But as our doctors would tell you, the chemo is usually relegated to much later in their treatment journey. So we're not anticipating a lot of chemo. So almost a pure second-line population. And then Mark maybe can guide on data readouts and enrollment.

Sure. Enrollment is going very well. We continue to push. We're guiding towards back end of this year to get completion of enrollment. And then we've just estimated 12 months just to share because we really don't know. And so that would be back end of '27. So that's as much as the crystal ball that I know.

And Doug, you're right, it's event-driven, bigger event-driven. So that we'll have to let the game play out.

David, maybe and I'd like Seth's input on this as well. In the second-line setting for patients who progress on a CDK4/6 inhibitor, whether we are using, let's say, fulvestrant plus a PI3 kinase inhibitor or we're using a CDK4/6 inhibitor combination or single agent. One of the things that we typically see is median PFS, as Seth said, but patients really don't -- they say what the heck is a PFS, right? And what they do can relate to is whether the tumor shrinks. And 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. But the response rate was pretty remarkable, it's 55%. And patients can relate to that, that is my tumor is actually shrinking. And so again, I think that's another thing, and maybe that speaks a little bit to that synergistic aspects of these 2 drugs together that Seth was talking about before.

I agree and that's quite a high marker for this type of line of therapy in endocrine-based treatment. And 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 getting up into the 60-ish percent. You would say probably if we were meeting with a company designing a trial and you're hitting response rates in the 20% to 30% and a median PFS above 6 months, you're saying, okay, like let's go. So that would be far in excess of those benchmarks.

Operator?

That wraps up our Q&A.

Okay. Well, 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. So let me go ahead and turn it over to Mark to close this 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, we're just understanding the mutations, the genotype and how important it is to have novel therapies in this space. What today's discussion reinforce is 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 differentiated 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 want to 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, investors, 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.