All right. Good morning, everyone. Welcome to our next session, and welcome back to the Cantor Healthcare Conference. My name is Eric Schmidt, and I am joined by my colleague, Dan Bronder. We are delighted to be hosting this webinar with LeonaBio. We have got from the company, Mark Litton, the company's President and CEO, as well as Dave Portman. A consultant still? I do not know how you introduce yourself.
Full-time helper.
Something. Full-time key-
Jack of all trades.
Jack of all trades and key managerial team member. Thanks, guys, for being here today. Mark, you're still relatively a newcomer to the public markets. Why don't you give a two-minute overview on the state of the company for those who are a little bit less familiar?
Sure. First of all, thank you so much for the invite. It's been an amazing conference. Those of you that don't know LeonaBio, it's recently a new company. We started last year. Leona is lioness, and truly represents what we do. We're fiercely courageous, but leading through collaboration of the pride. Nothing represents that more than the drug that we brought in license with lasofoxifene. Lasofoxifene is a truly unique endocrine therapy. We really believe in the second -line metastatic breast cancer space, that it can become the partner of choice. We will talk more about that. We brought in lasofoxifene from Sermonix. We have the father of lasofoxifene, David, with us. It was essentially a redo of Athira. We were led by Commodore, Perceptive, TCGX, raised about $246 million.
I'd like to give credit to the Cantor banking team because they helped us for a year to come up with a late-stage asset of lasofoxifene. We're just so excited. Phase III is going well. We can talk more about that.
Great.
Just a little intro.
Lasofoxifene has been around for a long time. Remind us of the history here and the twist of turns for this molecule.
Yes. My familiarity goes back almost two decades. I am dating myself. I was an advisor to Pfizer on their program, largely focused on prevention, a PI on five of their 11 phase II and III trials. It is a very well-characterized molecule. They deprioritized it after the Wyeth acquisition in 2009. While the drug went through full development for osteoporosis treatment, it was a very potent anti-resorptive. It actually had two phase III trials that showed that it treated urogenital atrophy and decreased new- onset breast cancer. It was a remarkable drug for preventive health strategies. Unfortunately, it never really got to see the light of day. Rights were returned to Ligand, and that is when I founded Sermonix and in-licensed it and discovered very coincidentally that it was the most potent molecule against ESR1-mutated cell lines.
That is when we became from a women's health prevention company to a precision oncology company, taking it through phase II studies, showing activity in monotherapy and in combination. Then when the phase III needed to be funded and operationalized, that is when the opportunity to join forces with Mark and Leona materialized.
Okay, we are going to get into more details around the development and the ongoing phase III, but this is, of course, a SERM, and many in the audience who are on the webcast are more familiar with SERDs, so put that into context for us.
Yeah. We're thrilled to be the only pure SERM, or selective estrogen receptor modulator, in late-stage development for advanced breast cancer. It's a very crowded SERD space. The reason originally was because these mutations of the estrogen receptor become ligand- independent, so logically it made sense to use a protein degrader to eliminate that receptor. What we found was that by binding with high affinity to those mutated receptors and inactivating them, putting them into an inactive conformation, we could do just the same, in fact, potentially better because of lasofoxifene's potency. It's the most potent small molecule. Even though it's not a degrader, it's more potent than all the degraders in development and approved. It also doesn't indiscriminately antagonize healthy estrogen receptors.
Coming from that women's preventive health world, I can certainly tell you that antagonizing estrogen in these women who are suffering from breast cancer can lead to very poor quality of life. So we think we have that unique advantage by not degrading or antagonizing estrogen receptors in the brain, the gut, the urogenital tract, but being a potent antagonist at the breast. It's the best of all possible worlds, and uniquely differentiated from the degraders.
And maybe Mark, one more high-level question before we get into the weeds. When you look at the story today and investors' attitudes, what do you think is most underappreciated or misunderstood?
Well, I think there's a lot of emphasis on monotherapy. What's interesting, the more we've interacted, to keep in mind, just to set the stage, w e're dealing with a complex heterogeneous tumor type that in the second-line setting, you have gone through AI, probably combination with CDK4/6, and there's uncertainty when you get that resistance, what do you do? A lot of discussion has been about monotherapy and a lot of groups trying to go front line. But interestingly enough, I think what's underappreciated is combo is really what's needed. Not only do you have to block the estrogen, but you need to do targeted therapy as well. And the other underappreciated aspect is you can re-treat once you've had resistance with your ribociclib or palbociclib up front. You can treat with abemaciclib, is what we're doing, and you can change fulvestrant to lasofoxifene.
Okay, great. So maybe as we get into advanced breast cancer for these patients with ESR1 mutations, second-line patients in particular, what is sort of the alternative or available therapies? What is the standard of care today?
It's a really shifting landscape, right? And that's the big challenge in designing trials, is to try to anticipate where the puck is going to be, not where it is right today. And I think we did that with the design of the ELAINE-3 trial, is that we knew that treatment was focused, as Mark mentioned, on combination therapy. The oral SERDs, we do have two oral SERDs approved as monotherapy, one PROTAC approved recently also as monotherapy, which all give roughly 3.9 - 5.5 months of PFS. But we've also discovered, and certainly the ELAINE 2 trial, our phase II trial, showed that you get a lot more activity, as was mentioned, with these multiple resistance pathways with a doublet therapy. So we achieved 13 months of median PFS in heavily pretreated patients with ESR1 mutations, all prior CDK, half with chemo, 80% also with fulvestrant in addition to AIs w hich really led us down the path of focusing on a combination strategy.
So right now, there really is no combination approved for the treatment of ESR1 mutations. Imlunestrant- abemaciclib has Category 2A NCCN guidelines. evERA, we know with giredestrant and everolimus, had a positive study and has a PDUFA date in December. But we feel that with the level of evidence that we're going to generate from the ELAINE-3 trial, we'll have the definitive doublet to address this very common mutation in patients in that second line. So right now, if you have an ESR1 mutation, the choices are monotherapy, potentially some off-label combination use. But we really want to provide that definitive high level of evidence. Hopefully, Category 1 NCCN guidelines is a combination of choice for the patients who have developed that resistance mechanism.
And maybe just sticking with the current treatment landscape, you already mentioned the potential off-label use of the approved compounds. What is your sense from KOL work that you may have done? How many patients are receiving monotherapy, SERDs, or PROTAC versus off-label combinations? Where would you think is the bar with fulvestrant plus abemaciclib in the control arm? Is that already being used in the second line?
Yeah. So fulvestrant- abemaciclib was our chosen control arm, which we were very proud to have done because the single-agent endocrine therapies as a control arm are certainly not standard any longer. It's interesting because fulvestrant was thought to be the standard of choice in the second line until it really only gave patients roughly two months of median PFS, basically, on average, progressing at their first scan. So at that point, it was very clear that that would be unfair to patients to randomize them to a single agent. So they get either fulvestrant and abemaciclib or lasofoxifene and abemaciclib. Historically, fulvestrant and abemaciclib actually can perform well, right? In post-MONARCH, six months, most retrospective analyses show that it's five to six months, which is as good or better, in fact, than the SERD monotherapy. So we feel it is a reasonable comparator.
It will also tell us what the contribution of lasofoxifene's component is to that doublet. If we can show significant improvement adding lasofoxifene to abemaciclib rather than fulvestrant to abemaciclib. We hope to show double-digit PFS. So if it's six versus 10 or 11 months, six versus 12, this would be ideal scenario. But the study's powered to show at least a three-month difference, which would be very clinically meaningful.
Before we get too far into ELAINE-3, you've got two prior trials, ELAINE-1 and ELAINE-2, and it's probably not worth. I think you already recapped the efficacy from ELAINE-2, but maybe recap the safety from both. Of course, this class of molecules, SERMs, has been confounded historically maybe by VTE risk. So what have you seen there?
Yeah. The ELAINE program, we had three trials, ELAINE-1, ELAINE-2, and ELAINE-3. ELAINE is evaluating lasofoxifene in ESR1 mutations. It is actually also named in memory of Dr. Elaine Nemzer, who is my co-founder's sister, who we lost to metastatic breast cancer at the age of 47. It is not simply an acronym. The team is incredibly dedicated to improving the lives of these patients. ELAINE-1 looked at lasofoxifene compared to fulvestrant. It was a small randomized phase II study. While it was numerically superior, it was not stat sig as would be expected with 100 patients, 5.6 months versus 3.7 months, which is very competitive with the oral SERDs. As I mentioned, five to six months is just not good enough, and we realized that we needed to see if lasofoxifene could be combined with a targeted therapy.
We felt that the optimal CDK after CDK would be abemaciclib, because the trends were that palbociclib and ribociclib were the frontline CDKs, so it made sense to switch to a different one. Abemaciclib has broader spectrum. It hits CDK4 harder, and we know that the CDK4- selective drugs are now certainly being looked at because of that benefit. It also hits other cyclins. We really felt that that was an opportunity. Lilly was very helpful in collaborating with us, supplying drug for both ELAINE- 2 as well as the entire global ELAINE- 3 trial. That is an excellent collaboration that we have with them. That is, as I mentioned, heavily pretreated patients with 13 months of median PFS over doubling the monotherapy. We saw no thrombotic events in the ELAINE- 1 study. Lasofoxifene is a SERM. It is a class effect.
Doctors are very familiar with treating the patients with tamoxifen, raloxifene. We know that they do carry a slight increased risk in thrombosis, but manageable. It is usually a manageable clot with anticoagulation. Patients can stay on a therapy that is benefiting them. Most of the oncologists we have talked to say that we know that abemaciclib carries some thrombotic risks, so long as it is not significantly amplified by lasofoxifene and is manageable. It is certainly something that they are comfortable dealing with. Low to mid-single-digit thrombosis in abemaciclib was seen in post-MONARCH. We do not expect to see much difference with lasofoxifene in the ELAINE 3- trial.
What do you think is an acceptable rate of VTEs?
I think mid-single digits is what the docs are comfortable with. I think if you're starting to see double-digit incidents, that may be concerning that the patients who are benefiting may be exposed to greater risk. Then I think patient selection is key, right? Some of these patients, healthy, non-smokers, not obese, no risk factors. They can really triage the right patient to treat even with any perceived risks. We're optimistic that it'll be a very manageable and tolerable adverse event.
Just to clarify, mid-single digits, all grade, Grade 1, 2 VTE?
Interestingly, the majority of the events we've seen have been asymptomatic and identified during restaging scans. They are very manageable. We have not seen, fortunately, any Grade 5 events. I think that'll bear out in the large data set. The advantage of ELAINE- 3 is it's going to be the largest combination trial in the second- line for ESR1-mutated patients of its kind. It has abemaciclib in both arms. We'll really be able to tease out these safety signals. All the other combination studies to date, other than evERA, have been in data sets that have been pretty small.
Maybe a last question on the thrombosis risk. Is there anything incorporated into the ELAINE- 3 protocol to mitigate risk or to guide physicians how to deal with these incidental findings?
Well, we are allowing patients with a remote history, who are anticoagulated. We feel that those patients are at low risk for recurrence because they're being treated and fully anticoagulated. We are recommending that if they're going to be immobilized for a prolonged period of time, they should hold their lasofoxifene, and to be aware of potential hypercoagulable states and avoid those patients in screening and enrollment.
David, you're already giving us the basic construct of the study, doublet with lasofoxifene versus fulvestrant- abemaciclib doublet. Any other details you want to share? Can you talk a little bit about, for example, the statistical design?
Yes. The unique design is that it's the only fully enriched ESR1 trial. A lot of the trials that have been done have stratified for all comers and ESR1-positive patients. It's really going to define the target and addressable population that we think the combination is suitable for. Patients who've progressed after an AI with either palbociclib or ribociclib and have developed an ESR1 mutation detected on Guardant360, which is the clinical trial assay. It will be the companion diagnostic. The patients need to have been at least on their first-line therapy for six months, so they, by definition, have some endocrine sensitivity. The assumptions are that we're shooting for a hazard ratio in the 0.7 neighborhood, 0.68, and that would be roughly that three-month effect size that I mentioned.
Six versus nine would certainly be a highly positive study, and we're hopeful that we can see even a greater delta between the two arms. That gives us 90% power. It also gives us alpha to look at objective response rates and even OS. Given the 600-patient sample size, OS is always a challenge. It's largely a safety endpoint. The study is protecting from a Type I error, but given the size of the trial, there's a possibility that we'll have enough alpha if directionally we see that, which would be tremendous.
You've mentioned the size of the trial. Remind us what the sizing is.
It's 600 patients randomized 1:1 , so 300 in each arm. Just to give you a perspective of that level of evidence, EMBER-3 had roughly 55 patients on their doublet who had ESR1 mutation post-CDK. evERA had 100. So we are 3x -6x bigger than the trials that have been conducted to date.
What's the latest on enrollment?
It's going well. We just publicly, a few weeks ago, announced that we hit our 500th patient. We're starting to see the hockey stick, which is good. So we're in the last push. We have over 200 sites, and we're encouraging everybody to enroll. The goal is, and I think we're going to hit it, finish enrollment by the end of the year.
Okay. Then event-driven from there.
Event-driven, yeah.
You expect the number of events to be achieved?
We are giving it roughly 12 months. But again, it is up to the patients and how they do, right? When they get a progression event. It is by blinded independent central review, so we have to obviously get those results from the core lab to adjudicate a positive event. So 285 PFS events by BICR.
Do you need a number of survival events in order to unblind or to file for approval?
I don't believe so.
Prevent that Type 1 error? No?
Yeah, I think that we're going to have potentially, I think, 40% of the survival events at the time of the primary analysis.
If we're fortunate enough to have a positive study, what do you think the implications are here commercially? Where's the best spot for this drug?
Well, I'll start, and then you can go. Our strategy is going to build. We would love to become the gold standard in that second-line metastatic space, starting with the ESR1 mutation population. There's no reason why that can't be expanded. If you just think of fulvestrant and its partner, you could also think of lasofoxifene. As we think of expanding, we could also be thinking about the other side with the PIK3 kinase and other combinations. Just in the second-line ESR1 mutation space, it's a $1 billion opportunity.
How do you get there, Mark? Ballpark numbers of patients.
It's roughly 20,000. If you take 20,000 patients and go from there, it really doesn't take that much. Keep in mind, if one has double-digit PFS, patients will be on for roughly a year, if you estimate in real world. That's where you get the numbers.
Do you think that PFS is a good proxy for the duration of therapy that patients stay on?
It's probably, I think in real life, it goes longer than that. Just to share. That's my personal take.
Latest pricing benchmarks in the space for those who have been following it maybe a little less rigorously?
Roughly $20,000, I think, in that ballpark. We're still early days on our pricing, but I think that's where the latest SERDs are in that price range.
There's a lot of other activity going on in the space. We get asked about it all the time. I know you guys get asked about it all the time. What do we make of whatever trial you want to start on? Why it matters or doesn't matter here.
Well, I think the ones that are on the near horizon is evERA, right? We think that the first combination to be officially approved, right, not off-label or 2A evidence for NCCN guidelines will be giredestrant and everolimus. I think that's great for patients because now the broader oncology community does have a combination that they can comfortably prescribe without knowing all the data and the small studies and having to get prior authorization and step edits. But the challenge there is that everolimus is a difficult drug to give, right? It has high rates of stomatitis, pneumonitis, and management issues. I think doctors want to use the CDK4/6 therapies as long as they can. That's why I think that with lasofoxifene and abemaciclib with a positive trial would be much more attractive than an everolimus-containing doublet.
I think that the fact that imlunestrant and abemaciclib right now, obviously, just with NCCN guidelines, is available. But frankly, imlunestrant itself has high rates of GI disturbance, right? Very significant diarrhea as a monotherapy, 10% grade 3 diarrhea with abemaciclib. It's the biggest challenge with abemaciclib management. We didn't see that in ELAINE -2. We don't have independent GI disturbance with lasofoxifene, so we don't think that that's going to be the challenge. Additionally, lasofoxifene in ELAINE- 1 demonstrated improvements in vaginal and sexual health. I mentioned we had done two phase III trials that this drug actually can treat menopausal vulvovaginal atrophy. From a quality-of-life perspective, these are patients that want to remain on all oral regimens, continue to live full lives.
We think a drug that adds and enhances to quality of life doesn't have some of the side effects of an everolimus-containing regimen or more challenging GI disturbance as potentially the imlunestrant- abemaciclib doublet have, really puts us, I think, in the best possible position as the doublet of choice for ESR1-mutated breast cancer patients in the second line.
You've already alluded to the oral preference or the preference for oral drugs by patients. Let's maybe address the other elephant in the room that is in PI3K wild-type patients, the VIKTORIA-1 trial. How do you think about that as a potential headwind in the ESR1 mutant space?
Yeah. We haven't seen their data on ESR1 cohort, the ones that are wild- type PIK3 but with an ESR1. Certainly, we haven't seen any doublet mutations with both an ESR1 and a PIK3A alteration. We think we can have reasonable efficacy in patients that have the co-mutations. We know that when they only have an ESR1 mutation, we think we'll be superior to what patients can get with gedatolisib. Gedatolisib also has very high rates of stomatitis. Weekly infusions really do tie these patients down to an inconvenient treatment schedule. I think it's really good for those patients because right now, the patients that have no alterations have limited options. I think that's really groundbreaking, and I give credit to gedatolisib for the very positive trials they have. But I think the route of administration will pose some challenges to the community oncologists.
The drug's been around for a long time, so maybe just remind us of the IP position and exclusivity.
Yes. Lasofoxifene has been around. It is never been commercialized or marketed, so there's no potential for off-label prescribing. It is a new chemical entity. In the U.S., the very minimum, we would have the five years of regulatory exclusivity plus a 30-month stay, so seven and a half years where it cannot be touched. But really beyond that and critical to that is we have exclusivity for the use of lasofoxifene in ESR1- mutated breast cancer out to 2042. The reason that those patents, we feel, are very strong is that the discovery was made totally by chance. This wasn't something that we tried to look for. Where is there space within the previous patent estate that we could find something? This was a discovery at Duke University that lasofoxifene had very unexpected activity. As I mentioned, these mutated receptors, they thought needed to be degraded.
When a drug that actually has mixed estrogen agonist/antagonist activity had the greatest potency against the ESR1 mutations, that was felt to be novel and enabled by all the patent offices that we have been in front of. We feel very confident that out to 2042, we have a nice runway of exclusivity.
Okay, maybe we just got a minute or so left. Perhaps you just conclude, Mark, with the cash runway and milestones over the course of the next 12 months.
Yeah. We ended last quarter with $51 million in cash. We're burning somewhere in the neighborhood of $15 million-$17 million a quarter. Again, the way we did our deal, we have Series A warrants that we're hopeful that will come in towards the end of this year. With that $146 million, it gives us plenty of cash all the way to 2029.
Upcoming milestones to be mindful of.
Finishing recruitment. We are pushing really hard. The other will, of course, be the data readout.
Great. Well, thank you, David, Mark, for sharing the LeonaBio story with us. Very interesting.
Thank you.
Appreciate you being here.
Thanks so much for the invite. We really appreciate it.