Atossa Therapeutics, Inc. ($ATOS)

My name is Mike King. I am the senior biotechnology analyst at Rodman & Renshaw following the biotech sector and I had Director of Research here at Rodman. I've got the honor today of having a call with the esteemed Dr. Laura Esserman from UCSF, who I will introduce in a moment. We're going to be talking about Atossa's lead program, (Z)-endoxifen and its role in benefiting patients with breast cancer. Also on the call with me will be Steve Quay, who's the Founder, Chairman, CEO and President of Atossa. He will not be making any formal remarks, but if we need him to jump in, then we would be delighted to have him join us as well. So more...

So I will jump in and just say thank you, Mike. Okay. Thank you, Dr. Esserman, for joining you. This is -- I really appreciate this.

Now I can't see Laura. Let me just see if I can do this. I see [ Harrison ]. Laura, are you there? Can you say hello? Yes, I'm not seeing her. No. I'm not -- this is not working. Harrison, can you see if you can let her in? There we go. Success.

Well, I'm joining -- let me figure out how to get off this. I have a new -- okay. I have a new tool in my office that has a screen where I could just join directly, but it's not working. I mean, I could hear you. I could see you, but somehow didn't register me.

Well, now we see you and now we hear you. So we are greatly relieved. So thank you for joining us, Laura. Sorry for the informality, Dr. Esserman, but I feel...

That's fine.

We've bonded so well over the last, I guess, 2 years' time. But let me do an introduction so we can dive into the heart of the matter. And let me -- for the audience listening in, I'd like to introduce our guest, our special guest, Dr. Laura Esserman. Dr. Esserman is a surgical oncologist and the Director of the UCSF Carol Franc Buck Breast Cancer Center, where she spent more than -- where she has spent more than 30 years at the intersection of breast cancer surgery, clinical research, and health systems innovation. She also -- she holds an MD from Stanford University and an MDA from Stanford Business School. And I know people who attended MBA school with Laura, and she's equally remarkable to the business people as she is to her clinical colleagues. But it's a combination that's rare, but it definitely defines how she thinks about clinical problems in the world of breast cancer. Dr. Esserman is a founder and principal investigator of the I-SPY trial, which many of you know, and the founder of Quantum Leap Healthcare Collaborative, a not-for-profit organization that serves as an honest broker between industry, academic investigators, and the FDA for drug development in breast cancer. And I will say FDA has a great relationship with Dr. Esserman. Early data from I-SPY has supported multiple FDA approvals. Dr. Esserman has been recognized by Time Magazine as one of the 100 Most Influential People in the world. And again, I can attest to her intensity, dedication to the cause of breast cancer, and bringing better therapies to patients. I love to tell -- in fact, I was telling the story just to Dr. Quay before we started of how I did a Zoom call with Dr. Esserman several months ago while she was still in her surgical scrubs. I had to wait 10 or 15 minutes for it, but it was well worth it. But if that gives you some of the idea of the depth of her character, I think that is a good summary of that. So Dr. Esserman, thanks, and welcome. Thank you for joining us.

Of course.

Okay. So I mentioned in the intro, your -- sort of your intersection between your business training at Stanford and then your medical and scientific training. And you've built probably the most recognized breast cancer program in the world at UCSF. So what were the frustrations and the hurdles that you saw with patients that you couldn't help or where the process wasn't working the way you wanted it to that convinced you that the traditional model of drug development was simply too slow and too imprecise?

Well, I think part of it is that while you can have innovation and ideas, the pace of execution is quite slow and the number of steps it takes to put something into practice is enormous. David Dietz did a study of the number of steps it took to get the cooperative groups trials open from a protocol to an open enrolling protocol. And I think CALGB, which is the group I was part of, had the shortest number, but it was 336. And people sort of thought that was funny. They had assembled all of the steps in like a series of poster boards across a huge room. And that's not where we should be spending our time. And I think that what I also saw is that the reason why we have a protocol for every single idea is because that's how credit is given out and you get to be the PI of a protocol and so on, but that's actually not a good reason to have another protocol. And I felt like there was so much opportunity for innovation in the process, just the process of how we did trials, let alone the idea of how we are innovative and moving new ideas forward. The pace of change, like just for example, I guess the idea is second, but just this idea of how many steps it gets to open things up, how long it takes to get your first patient enrolling in a trial that just is open was kind of ridiculous, the fact that every IRB had to be used. So I thought, "Okay, what we need to do is develop a platform trial. You have one trial, you can drop drugs in and out as you need it," because it really is the same drill over and over again. It's sort of what Starbucks does. It's what all the semiconductor industries did, trying to think about how do you make the process seamless. And even how could you go from a Phase II to Phase III or how can you move from one idea to the next. And so that's really how I-SPY started. And also, I felt like traditional statistics were also not the right way to go that, really, what you wanted to do is learn as you go, your every experience, your every piece of information adds to your understanding. And so we started with a Bayesi and adaptive trial at the time I was working with Don Berry and trying to work with figuring out how you can learn as the trial proceed. And that's how I-SPY was developed. And what we did was we took high-risk women with Stage II and III breast cancer and said, "Okay, breast cancer is not one disease, but we still treat it as one. So how can we say -- let's profile them in different ways, take -- say that we're going to define the heterogeneity from the get-go, and we're going to look in the different subsets, and we're going to see how different people respond. We're going to do everything upfront before someone goes to the OR." So if someone is at risk to die of their disease, surgery isn't going to cure them because surgery takes out the local disease, but it doesn't do anything about it showing up in your liver or your bones or some metastatic site. So really, what you want is an early indicator that something is working. So again, learn the course of care. If you give adjuvant therapy, you're giving it to everyone and you have to wait to accrue everyone and then wait another 5 years to find out how it works. That seemed enormously inefficient to me. And the order of therapy didn't matter, so you could switch it up and say, "Okay, let's do it that way." And so if you do it that way, you can have drugs come in and out. You can have -- we eventually, over time, have gotten a central IRB. So we have gone -- in the last 15 years, we've evaluated 35 different drugs. And we now have a central IRB process where we put an amendment in, it's 3 weeks to the IRB approval and, simultaneously, at 4 weeks for the FDA. So in a month, we have that arm of the trial enrolling in 48 sites at full tilt. And so we're currently putting 500-plus patients on a year. And then we realized also that the high-risk but molecularly low-risk patients that we screened out of I-SPY who really don't benefit from chemo should also be studied, and we should be trying different endocrine therapies for them. And while we don't have an early endpoint for the high-risk, fast-growing cancers, we know that the early endpoint should be whether or not the tumor goes away or mostly goes away. And we're working on improving those endpoints so the FDA will have an acceptable early endpoint. And our knowledge turns are 3 years and not 17. But now we're trying to do the same thing in that endocrine space, and we're going to try and go backwards into that to try and figure out what is the right goal for what we want to see a change? So most women will do okay with endocrine therapy, but a certain number of people will not. And I think the most important thing is, like especially in the endocrine space, is improving the tolerability of our treatments. One of the reasons I like working with Steven and with Atossa is because endoxifen is so incredibly well-tolerated. This really matters to women. You've got drugs that are standard of care that after 3 years, 60% of women stop taking. That should tell you something. And we need to work harder to find things that are not only more effective, but more tolerable. So I would say that the -- it is going on of what we're trying to do is get the right drug to the right people at the right time and to have early endpoints that continuously guide how we learn and how fast we can move. And we're trying to put a lot of pressure on the FDA to really move forward at that pace. They want to test A versus B in the old way, but that's actually not what women need. That's not what the field needs. And as an independent, I'm on no advisory boards. I don't take so much as -- I don't take anything from any client, and that's not why I do things because I'm here as an advocate for my patients and field. That's the role that I've chosen to play. And I want to try and make things better from screening to treatment to policy. So...

Maybe that's a good point if we could just maybe take a quick step back. So if I heard you correctly, and then I just want to set the context for our listeners who may not be as familiar with the sort of the in-depth aspects of the things you're talking about. We will definitely come back to that. But it sounds to me like I-SPY was the original protocol concept using some of Don Berry's Bayesian statistics. And then Quantum Leap was created or Quantum Leap and I-SPY created at the same time?

So, no, Quantum -- so we started with the foundation for the NIH. So I was working in the cooperative groups, that's where I-SPY 1 had been done. And I have this idea that by starting with MRI, I worked with Nola Hylton, who was the physicist who developed the sequences for what became breast MRI. And that's how -- and she had come to me and said, "Well, how do you want to use this?" And I said, "Well, I want to look at these people who show up with these big cancers, see if all the tumors look the same." Lo and behold, they did not. And I said, "Well, I want to treat some of these people first and see what happens." And do they all respond the same? They did not. So saying that everyone should be treated the same way is clearly wrong. And we needed a framework for that. And I tried to set up to this cooperative groups a way in which we could do this and do it faster, and there was a period of time that I wanted to change one of the imaging endpoints and it took 2 years to get it approved.

Wow.

And I was just curious. And I think...

I would imagine there's a lot of turf battles that happened...

Like there was like -- it just was lost and the whole idea is like once you've got the engine running, the whole idea is to keep it running.

Right. Right.

And when people get distracted and do something else, that's when things fail. So they told me I had to learn to wait my turn. And I said, "Well, that's not going to ever happen." So I decided...

They don't know me very well, do they?

Exactly. So I went to Anna Barker, who was then Deputy Director of the NCI. I'd asked Jorge Gomez because this came out of Specialized Program of Research Excellence, SPORE. And I said, "Who's the most innovative person at the NCI?" And he said, Anna Barker. So I went to Anna and I said, "We have this idea," and I brought Don in, and then we started this protocol. And she said, "Well, let's put it through the foundation from the NIH, the Biomarkers Consortium," which we did. And the minute Anna left the NCI, everyone said, "Well, because I thought it was too risky," because we started before we had all the money we thought we needed to run the trial. And at the time, we weren't charging anybody for it because it's a brand-new thing. Everyone said, "Well, you'll never get more than one company to put their drug in at a time." It's literally not true since we've had 35 of them. Anyway. So they tell me, "Well, that's it. It was a great success. You're done." I'm like, no, no, no. We're just getting started. And in the meantime, at Quantum Leap, I had started this as a way to try and improve the way we exchange information because I feel that's also very wasteful. People gather information and they bury it notes, and it's not in an organized structured form that can be easily exchanged and work for quality improvement, registries, trials, and care. And care was just as important as all these other things to be good and high quality. So we were working on tools for that. And the Board said that they wanted to do something more important. And I said, "Well, how about becoming the sponsor for I-SPY?" And they said, "Okay, great." And that's how that was I-SPY in end of 2013. And one of the things that's great is I got a lot of people that from the business world and people who are used to process improvement where the idea is how do you think about knowledge terms, and strategy, and efficiency, and management as a science. So what is the science of management? Where is there all this white space that you can compress and you can work on trying to make the process better? And so that's a lot of what we've been doing, the tools that we have, which is where you can take information directly from the EHR and have it go directly to the care. So the idea that you have electronic system where there's a person in the middle copying from one electronic system to the other also seems completely wasteful in an era when none of that should be required. So...

Well, it seems like it's been pretty successful. I mean the stats are impressive. 4,500 patients screened, 2,800 enrolled, generated 100 publications, 10 agents have graduated.

150 publications, I will...

Wow. All right. I got to correct that. All right. Sorry. Thank you for correcting me. And sorry, I lost my place. But -- and then you've also, I think, validated the PCR response rates as an important early biomarker. I-SPY also is best known for what it did HER2-positive and triple-negative breast cancer. But this ER-positive, HER2-negative luminal subtype has historically been the hardest nut to crack in the neoadjuvant setting. So with PCR rates that are pretty low. So what did that gap tell you? I think you started to touch upon it with your earlier comments about patients not responding as expected. Why did it point you to the need to rethink endocrine therapy as a backbone rather than just as an adjunct?

Well, I think that over the course of these 10 years, I would say that we have screened almost 6,000 patients. And the enrollment has -- now it's up at about 3,800 patients that have gone through both I-SPY 2 and now 2.2. So in 2022, in July of 2022, we changed the trial format to be something that -- we've changed the trial format to be what we call an adaptive design, not where the trial is learning so the next person gets the best treatment, but each person, their information is what you learn from and people -- we can individualize treatment within the trial. So if you have a great response after -- so we then said, "Well, I want to bring the new agents upfront and give novel therapies to patients before chemo," because the whole point of these novel therapies is to replace more toxic standard chemotherapy. And why are we testing them only in the metastatic setting where if they work, you improve disease-free survival for several months as opposed to when you get them upfront, you can actually cure somebody. So -- and you can prevent metastatic disease. So we get them upfront. And if you don't have a good response, you can go on to the next block of therapy, which is your standard taxane just -- and then you get the best treatment based on your subtype. And then if you still don't have a good response, then you go to the last block of therapy, which has doxorubicin. So what we are -- so there's 2 really important places that we're trying to change. So it turns out that some of the -- one of the most important things that's come out of this is that if you have an immune subtype, this is as defined by expression profiling. But importantly, we are understanding so that a lot of these are the proximities of certain types of cells to the certain tumor cells or dendritic cells. And those are patients where we can really get pretty good responses, and we can probably replace a lot of standard chemotherapy, antibody drug conjugates combined with immune therapies. But if you do not have an immune susceptible subtype, it is really hard to make a cold tumor hot. It's not happening. I think it's a completely different pathway. And we don't know that we can routinely do that. So it turns out that the Luminal B patients, these are high-risk ER-positive tumors that don't respond to the immunotherapy, they don't really have a good response to chemotherapy either. And that's true for the...

And there are no targets? Are there any targets there for the...

Well, there's estrogen receptor, progesterone receptor. I think we should be thinking about things like testosterone or androgen receptors as well. And combining -- the endocrine system is actually very complicated as well. We haven't really thought broadly enough about it. But I think that if you are not responding to the first set of standard therapies, that we should then be going to more interesting or complicated or combination endocrine therapies to see how we can do that or endocrine therapies plus looking at cell death or apoptosis, where you can make these interesting combinations. So in the meantime, we said, "Well, all these patients that screen out because they have molecularly low-risk disease where we know chemotherapy is not going to help them," notwithstanding, we still give it. But where we said, "Okay, we're going to do 6 months of endocrine therapy first." And that's where I've gotten a lot of experience with endoxifen because that's one of the -- we've had many combinations of endoxifen in that trial. And then trying to think about, "Well, what about the patients who don't respond to chemotherapy or the novel therapies upfront. And these other patients, maybe we can begin to start to think about how we make a change." So Luminal B cancers, we have not had an improvement in since we started, whereas the overall complete response rate has gone from 19% to close to 55%. So we've almost tripled the chance that we can make a tumor go away, but that's largely driven by these immune subtypes. If we don't make -- our goal was to get 90% of patients to a complete response. And we're not going to get there unless we do something about these Luminal B cancers. So we have to make a change. Excuse me. So I think that one of the things that we -- sorry.

Bless you. Is that pollen [ day ]?

It is, Mike.

Yes. I sort of think...

Yes. So that we have to really think differently about -- sorry, how we're going to go after these tumors. And I think the important thing for me is not only having something that's effective, but having something that is less toxic. And it's really, really important. I think in the endocrine field, our standard therapies actually are pretty hard on women. The aromatase inhibitors cause a ton of joint pain. And at 3 years, 60% of people stop taking them. We give all women, who are young, we shut their ovaries down, and that is actually pretty tough on people. As one of my patients used to say, "Yesterday, it was 36. Today, I'm 86."

You're right. I have menopause, right? Yes.

No, it's not menopause, but creaky bones, hard to do things at 86 that people feel like they've lost their vitality and so on. So it's very hard. So looking for things that are effective and less toxic is hugely important. Hugely.

Right. Well, the one molecule you didn't mention is tamoxifen and then that's, obviously, one that creates a lot of -- women are supposed to stay on it for 5 years, 10 years in some cases, but that's really tough as well. I'm just wondering the...

So one of the things that's very interesting, I think, about tamoxifen is that my colleague in Italy, Andrea De Censi really showed that, especially in the prevention setting, that you can use lower doses, 5 milligrams and smaller doses, which is really much more tolerable. And thanks to my colleagues at [ Seo ], who had -- I think he was worried about the metabolism of tamoxifen and it's a long story, but he was very interested in looking at the metabolites of tamoxifen and endoxifen was one of them. And so I always assume that endoxifen would be just as toxic or more toxic than tamoxifen. But it is not. It absolutely is not. So that's -- I think it's clearly an effective strategy that is extremely well-tolerated by the way...

Well, do you want to talk about that? I mean it is the metabolite of tamoxifen and it seems to -- it's the business end of it, so to speak. It doesn't need to be converted, right, by CYP2D6. So do you have...

That was actually why I think [ Dietz ] really started on this because he was worried that people had differing metabolism, but the way in which you measured it was very complicated. It was really hard. So well, why not just start with the money business and start with that. And -- but I think what's interesting is that it turns out to be really extremely well-tolerated that's going on here. And so I think that -- and I want to say one other thing. So there's another trial that I run. I run 2 other big trials. One is called the WISDOM study, which is looking at a way of trying to change screening from a one-size-fits-all to a more personalized way of assessing risk and determining who needs risk reduction and who can have standard -- who don't -- the person who's very low risk doesn't need to start screening until 50 and the person who's at a very high risk needs to screen more frequently. So the WISDOM study, it's been getting a lot of play in the news, but it's -- I think partly because I was trying to do something to improve screening, most of the women who are in I-SPY don't have their cancers detected by screening. So we're missing the bad cancers, and we're overdiagnosing things like Stage 0 cancer. And so then I also started trial called RECAST DCIS. It's all about evaluating conditions for active surveillance that would be suitable therapy for Stage 0 lesion. So instead of doing surgery and radiation, I'm a surgeon, we should be using our tools wisely. But if someone just has risk factors, they should get endocrine risk reduction not [ SCR ] driven and not surgery and not radiation. And it turns out that this is -- so we have a trial testing 3 different endocrine therapies, endoxifen is one of them. And -- against the standard, most people are using Baby-TAM for that. So I have actually a lot of experience in RECAST also because we have 40 or 50 patients now UCSF on that trial. And I did a -- I started this with a long-time registry to sort of say, "Why are we operating on these people?" And doing active surveillance and finding out using MRI imaging is my calling card. So you can look and see if people just have lots of stuff lighting up everywhere on the MRI, they don't have focal surgical disease. They just have [indiscernible]. And so you can bring that down. So imaging is a catalyst for learning and figuring out how you can change. And so over time, we figured out how to write a protocol so that we could do appropriate management. And so one of the things that I'm impressed by is here, purely, these are people who are purely given like Endoxan or tam or whatever it is that they're given. So I have experience with how people tolerate this, whether it's a pre-menopausal or post-menopausal. And I can tell you that endoxifen is extremely well tolerated. Chemo...

How important are the sort of some of the -- again, the fact that it's the active metabolite, not the prodrug, the fact that it may degrade estrogen receptor, so it's sort of a SERM and a SERD, it hits PKC beta 1. Are all those things important to you as a clinician?

Well, I think what's -- I think at the end of the day, what's important is whether it works or not and whether people have side effects. And clearly, we know that it's worked, people have been able to stay on it. I mean one of the ways in which we tell whether something works in the RECAST study is if people stay on it, that means they're tolerating the medicine and they don't feel like they need to get off it. And they're not going to stay on it if it doesn't work to reduce the background on the MR and if the lesions themselves aren't coming down. So the fact that people can stay on it and they're recommend -- so the trial works that you get 6 months of the treatment upfront. And at that point, you can make an assessment about whether they're a good candidate for active surveillance and they can choose to stay on it. Now someone -- that's -- so that's the trial, the 6-month period, that's the key endpoint. But at that point, people have the options to stay on and skip surgery if they meet certain criteria. So there is your measure of tolerability. Someone who hates the endocrine therapy is going to say, "I'm not doing this. I'm going to have surgery." And so the fact that most people who are on it stay on it, I think, is very telling, not only that it works, but that it's very tolerable. Now I can't say anything about how it's for the whole trial because that's not -- we [ don't ] analyze that data ahead of time. But I think that in terms of -- for whatever reason, the side effects of tamoxifen, obviously, don't come from the active ingredient. That's really exciting because I find that even some people who are on Baby tamoxifen, which is much better tolerated than the full dose of tamoxifen, there are some people who really hate it and just can't tolerate it.

What's the dose of Baby tamoxifen? What is it?

5 milligrams.

5 milligrams versus?

Versus 20. Versus 20. And it's very interesting. In the NSABP trial, which was the first big prevention trial, P-1 trial that was reported in 1998, there were like 13,600 women on it, and they were randomized to tamoxifen versus nothing for being high risk. And other than hot flashes, the same number of women put on both arms. And -- but the tools that we use, which obviously weren't very good, showed that there really weren't side effects, particularly, but that's just not the experience that people have. And people really just don't feel well on it. And even at the lower doses, it is much better, but it's not gone. And I've told Steve this, I don't understand. It's so interesting to me. It's clearly not the active ingredient that is driving that toxicity. So if you can get rid of it, how fantastic that is. I mean, if you really want to make a difference, I mean, ER-positive cancers, the majority of women die of ER-positive cancer because that's the majority of the cancers that we have, plus we're doing a great job of the triple-negative...

Most investors don't realize that because HER2 or triple-negative have been where the big breakthroughs are, but the ER-positive is still the one that's the biggest killer.

Well, not only have we not made enough breakthroughs in that, the other ones, the HER2 and the triple-negatives, we're figuring out how to cure. But ER-positive cancers, we are not. It's just a huge problem. And we have to do better. We have to think of better combinations, better endpoints to figure out how to make a difference more quickly for these people. But how fantastic if we could do that without making people sick.

Right. Right.

Actually...

If I could just interrupt, Laura. I mean, to me, I finally realize that when you see what happens in the blood when you take tamoxifen and you have 20 different metabolites and you give them endoxifen alone and you just have one, I think it's one of those others that's causing a mischief.

Obviously, and it's -- so like I can't say I say, "Wow, what is the magic here? Why is this not causing side effects?" I was thinking, oh, this is the active ingredient, it's really people are going to have more hot flashes, really feel terrible, but they don't. So to me, like a drug -- so I think one of the things that's really important is how do we make an effective, tolerable agent absolutely to be something that's an alternative or the standard of care? So I think we have to think about this opportunity to do better. I mean, isn't that -- it's not what pharmaceuticals are all about...

Yes. Well, the tolerability is got to be a factor, but you can't sacrifice efficacy for that. I mean it's an obvious statement, but...

Well -- and so you got to think about -- so there aren't -- there are some surrogates like drop in Ki67.

Well, I was just going to ask. Yes.

You can look at the background enhancement and whether that goes away. That's another indication of endocrine sensitivity and whether the lesions go away. All those things are happening. But if you want to wait the 20 years to really prove it, we'll all be dead. So I think we have to work harder to figure that out. I think one of my ideas is to kind of work backwards into trying to figure out what that MR volume threshold is and what the residual cancer burden is for the -- for the lowest of the -- lowest risk of the I-SPY 2 patients, people who have that low-dose Luminal B cancer. So I'm working on trying to come up with an endpoint. I mean it will take time and the FDA is not going to like it first. But I think it's something that we can do, and we can come up with. But we must really work towards saying, "We need early markers of effectiveness. We need early markers of measurements of tolerability." So we measure lots of tolerability in lots of ways, including a tool called FACT-GP5, which is other, which I think is a very, very good, simple way that's very comparable across all treatments to say, how are you feeling? How are you doing? How bothered are you by symptoms? And so I think that's super important.

Can we tether this to some data because you did present the I-SPY 2 Endocrine Optimization Pilot at San Antonio, where you're combining endoxifen with abemaciclib and elagolix in the newly diagnosed ER-positive, HER2-negative breast cancer patients. Can you walk us through what you found, particularly you mentioned earlier, Ki67...

We haven't presented the elagolix study yet. But that is something that I am super, super, super, super excited about. And I have to say, kudos to Steven for agreeing to this combination that we were trying to give endoxifen at higher doses with abemaciclib, which is the CDK4/6 inhibitor. But we have seen a spike in estradiol, which can lead to cysts. And it's true. So everyone was saying, "Well, you have to give ovarian suppression." So -- and I said, "Well, I'm not ready to give up yet. So I contacted Hugh Taylor, who is the Chair of OB/GYN at Yale, who I had met through the work I was doing on this RISE conference, which we're going to come back to. And he said, "Oh, well, that's because you have to start the ovarian suppression before you start any of these medicines because otherwise, you're going to get a spike in the estradiol." And then he said -- and I said, "Well, Hugh, isn't there a better way? Isn't there another way that we could do this without causing full ovarian suppression," which is so hard and limiting. He said, "Oh, yes, absolutely, we've done all this work with elagolix, which is an antagonist that you can -- it's partial, so you could give half the dose." And obviously, this has not presented data. We haven't finished it, but it's -- we did 10 patients each. And I called this Steve and I said, "We've got this idea. What do you think?" And he said, "Great, let's do it." And he did it like this. We got an amendment in. We had it in 2 weeks. We are testing. And what's so exciting is that the -- so we are seeing the same drop in the cell turnover, the same drop in functional tumor volume. But the FACT-GP5, that how bothered are you by symptoms, is so much better. and women who are on the elagolix versus the ovarian expression. So I, to me, that's a huge win. I would really love to expand this. So it turns out it's actually there's not -- the amount of investment in women's health is not what it should be. Oh, Steve, I know what the right solution is. You should -- since they don't really care about elagolix, why don't you buy it? Why don't you acquire elagolix?

So I love you, Laura, but I have to say we're a public company here. And so all these comments are subject to...

Sorry.

Everybody else.

Sorry.

Right. It's fine. We'll just put that disclaimer...

Sorry about that. You can cut that out.

Let's set that aside for...

AbbVie says, oh, because we want AbbVie to help but their -- I heard from Dr. Taylor that they're not -- I mean there's -- I think women's health, the real innovative work in women's health is not going forward as it should. It's just not. [ They're not yet ] interested in.

Do you want to -- speaking of combination therapies, do you want to talk about endoxifen and abemaciclib? I know there was some -- a poster at AACR that the company presented, but is there a promise in that combination or is just...

Yes, absolutely. I think the thing that -- really the side effects from that really come from the abemaciclib, which is cause of diarrhea and can cause -- but there's no added toxicity whatsoever. And the combination appears to work just as well. So how we can measure -- I think that's what our group at I-SPY is really about, how do we refine these early endpoints so that we can show that these combinations really are working and that those -- that the early endpoints alone can be effective for getting things approved. So one of the things that's very frustrating to me when I see people looking at the selective estrogen receptor degraders, everyone is sticking with the old model of the adjuvant therapy. And again, when you give it -- when you do an adjuvant therapy trial, you have no idea how each person responded. You don't even have that as a baseline. And these trials are like $1 billion to show the difference between an AI and a SERD like -- and they take a long time. It just feels to me like not the most efficient way to move the field forward.

So what's the best patient population in which to use the combination with abema? And what is the early endpoint that you would seek? Is it Ki67 or something else?

Well, I think it's going to have to be a combination of endpoints. So I would say that what you -- where -- I think people who have small little tumors, there -- what you should just do is a tolerability study. And again, to show that the drugs are more tolerable. And I don't know. I think that because this is an active metabolite of tamoxifen, there may be -- maybe we should be thinking about showing equivalency so that you can get out on the market, so you can do more things more quickly with combinations. But I think that when you have people with more -- sort of more burden of disease, so Stage II and III, early-stage cancer, there, you want to try and give the therapy upfront. So again, we do everything in the neoadjuvant setting to try and measure those impacts. So you can see, yes, the cell turnover rate comes down, and there's a good -- a big body of literature that shows that if you can bring the cell turnover rate to below 10%, that, that really should be -- that's the predictor of outcome. That was the POETIC study that was based on a neoadjuvant cohort within the ATAC, the comparison of an aromatase inhibitor to tamoxifen. So as a combination, and they show superiority -- slight superiority of the aromatase inhibitor compared to tamoxifen and that's Ki67 and it turns out that in this case, tamoxifen, which is much more tolerable than an aromatase inhibitor, if you can get that same kind of risk reduction by looking at those early endpoints and you know it's a metabolite of the drug, I think that there is an opportunity to think about a strategy like this to try and go forward to get it approved as an option. I think it's so important because -- I mean, I just saw a patient in clinic this morning who just had stopped -- she had stopped her hormone therapy because it was just -- she just couldn't move her hand, she couldn't do anything, and it was so difficult. And she had a recurrence with DCIS, which, okay, that's not going to kill her, but she had a very bad cancer in the past. So we wanted to put her back on it. So we finally have run like a lower dose of exemestane, which she's tolerating okay. But it would be great to be able to give her a drug like this, that she's going to tolerate better. So I think it's so important that in order to get the benefit from a drug, you have to be able to take it. And more attention has to be paid. And I think the advocates can help us with this. I think we have to do a better job of thinking about how do we advance therapies that will really help people prevent recurrence of disease in a way that's very tolerable.

Let me ask you this question. It wasn't one I had prepared, but just sort of synthesizing everything that you've said so far. What -- obviously, this would be a great benefit to women with breast cancer if it were on the market quickly. You're doing -- you, with I-SPY and the different arms of the I-SPY protocols, are doing a lot of work. You've got a lot of ideas. We have a regulatory system. You're close to the FDA, but there's still a fairly rigid regulatory system in place. How do you align or how do you do sort of see what the fastest path through that regulatory system to get this drug to patients as quickly as possible?

Well, the first thing that has to happen is we have to stabilize the FDA. I think let's just mention the elephant in the room. Okay. And I think everybody who has any influence anywhere, it's really important to ensure that the FDA has independence and they get good people and that we can have meetings where we talk about early endpoints that when you come back or you -- whatever you say that you're going to achieve that when you come back with the data in hand, they say, yes. I mean that's going to be -- I think we just need to reestablish integrity and the ability of noninterference in the Food and Drug Administration's ability to regulate the drug industry. And I think that we are working very hard with the Oncology Center of Excellence to show that you can look at -- myself and I have a whole team of people working on early endpoints and how this can influence trial design, where we have really looked at how to improve the endpoint. So even in a high-risk setting, we've used complete response, PCR, as that early endpoint. FDA has not leaned in enough on that. And why is that? So when you really look deep into the data, one of the reasons for that is that if you have a near complete response, you have almost as good an outcome as if you have a complete response. So if you have a 0 versus everybody else, that's probably not the right cut point. So if you think that there's a hole from 0 all the way to 3 or 4, the cut point is probably somewhere around 1 or 1 and 2. So for hormone-positive cancers, it's more like 2, for HER2, it's 1.1. So we've worked on optimizing the endpoints and used the 2,200 patients that we had from I-SPY 2 to come up with these cut points, and we are now validating it in trials, we also established that residual cancer burden is a standardized way of measuring the amount of disease that you have that's left. I think one of the things that makes I-SPY good is that we have really -- our creativity comes from standardizing the way we evaluate every single patient, same full profiling of every tumor, making sure that the surgeons clip the spot so that when you say someone has a PCR, you know they have a PCR, making sure that people collect residual cancer burden in the way that Fraser Symmans, who developed this technique, intended it. We created this pool data set of 5,500 patients out of 10 institutions and showed again that the residual cancer burden is a really good predictor of individual outcome. Now where you get that hang up from the FDA is they're not looking for the individual outcome prediction. They're looking for a trial. And you have to be able to say that if drug A versus drug B is different. So what you need to do is find the cut point, not for all patients, but for the subtype of cancer that is more homogenous. So the HER2s are different. Even the luminal versus non-luminal HER2s are very different. And in the hormone positive, it's whether you're immune or not, but the majority are non-immune. And so that threshold is a little bit different. So that's too. So if we can show that these endpoints are very good at the trial level, we might be able to use that exact same endpoint even in the hormone-positive patients. And that, I think, would be a sea change in our ability to do studies to optimize endocrine therapy. And the thing is if you don't get a good response from the basics, then you can start adding things. And that's how you can rapidly work to try and say, I want to find things now that prevent metastatic disease, so they don't show up in 8 years with metastatic disease where you really are not going to be able to cure them.

Right. But then these -- just to be clear, these patients are not expected to go surgery though, right? These are going to be like biomarkers like Ki67...

No, no, they can go to...

They can go to surgery?

They go to -- yes the can because cancer...

Okay. So your PCR could be...

At surgery, but you have to give yourself a window of time for the endocrine therapy to work. Same thing for the chemotherapy, whatever. So the idea is, think about it this way. You've got a patient who's got treatment over a 5-year period of time. What you want to say is, okay, instead of operating right here, give part of the treatment and then assess the response right here. And we, by the way, do it with MRI along the way and then use that indicator to predict what happens out here. And that's what is going to -- that's what's going to accelerate [ knowledgesurance ]. That's actually one of the things that Andy Grove wrote this amazing piece in JAMA in 2007(sic) [ 2007 ] after he got prostate cancer. Founder and one of the CEOs of Intel. And he said, wow, a view of the -- this is looking at health care, a view from the outside. It's a scaling review of how we learn things and how we don't use early endpoints and how we want overall mortality as the endpoint and how we're doom to having really long knowledge turns, which he's completely right about. Well, actually, used to call [ loopty loop ] trial, but it was -- I was actually working with it before he got super sick. We were working on something for Parkinson's for them. But it was -- it's this idea that really was where I got -- I really did get the idea from I-SPY for looking at his philosophy, like I never put a product to the market without having the second, third and fourth version of it. And he -- they set up a system where they could constantly test and constantly improve. And that's what's changed the software industry, this huge learning engine. And so I'm trying to do that in medicine. And breast cancer is a perfect place to do it in. And so I have a penchant for drugs that work that aren't toxic and trying to figure out how to get them into the standard of care that we can build on and, really, affect change for women so they have more tolerable treatments that keep them from dying of their disease or suffering from their disease or the consequences of our treatment.

Right. And Laura, Andy was an investor in the gadolinium drug that I invented for the MRI imaging. So...

Is that right?

We've had a full circle, yes.

Yes. He's really a character.

He was a big benefactor of the Prostate Cancer Foundation when he was alive as well. Attended all the scientific retreats.

He's very tough.

Can the FDA deal with the loopty loop trial? I mean, again, where does it enter that process where somebody at -- in Cedar Oncology Office of Excellence signs their name on it and says, "This is now going to be available to patients based on this trial results."

Well, so I think the FDA still like the traditional trial of A versus B. And I obviously don't think that's the best thing. But I think what we're trying to do right now, I-SPY 2 is a signal finding trial. But when we find a signal, what we want to do is be able to do a seamless Phase III where you continue to -- that you try and replicate it and make it more standard with an agreed-upon early endpoint. And I think that where we are -- where we don't necessarily agree is they're like, well, people can get whatever adjuvant therapy they want afterwards. But if you don't -- if you have a great response, people aren't going to get adjuvant therapy afterwards. If you don't have a good response, of course, you're going to get more therapy. That's the same thing with progression-free survival in the metastatic setting. When someone progresses, people will say, "Oh, I'm sorry, I can't treat you. You're on a clinical trial." I mean that would be unethical. So why is that any different? So I think what you need to do is say, "Okay, anyone who gets this good outcome and doesn't get additional therapy as long as they have a 92% survival at 3 years or 5 years, whatever it is," I'll get accelerated approval...

Right. And the nice thing about -- the great thing about I-SPY is that you're not looking for a low signal. You're looking for a big signal that...

It's a big signal. And again, I think that we can be conveners. We are 48 sites. We have 200 investigators. We worked with 35 companies. I think what Rick Pazdur told me when he was there and...

Well, he may come back with...

He might come back. He might come back.

I think it's on the poly market...

So it's a prediction that he'll come back.

Yes.

Well, he want some guarantee of scientific independence. I'm sure.

Yes, I'm sure.

But is -- but what he said was, okay, bring the community along with you. And if you can bring the community along with you, then we're going to look very seriously at it. So that's what we're doing. We're bringing all the advocates. We're bringing all the companies, and we're trying to speak as a voice to say, "This is what we feel will be good for the community." I'm not doing it for myself. There's nothing in it, and I'm not, in any way, personally involved in making money from any of this. And so -- but that's not what I'm about. I'm about being a catalyst for change, good change, to be able to prevent disease and give people better quality of life and to get those effective, less toxic therapies on the market sooner at a time when people really need them and figure out who needs them. So we don't overtreat and we don't undertreat. That's the goal. And I think the field needs people like us who are the leaders of I-SPY that are...

Well, we should call you across multiple different tumor types. That would be amazing.

Well, I would bet you that within a couple of years, this model that we built is going to be very highly replicable.

Steve. Laura, I mean I got an e-mail from a woman that was in your -- in our trial, said, "My tumor shrank by 78%, and I won the half marathon in my age group."

Oh my gosh, that was a good thing.

Yes. And the thing is these people want to stay on the drug after 6 months. And -- but here's the problem for a drug that's not approved to be able to have to do an N of 1 and you have to be able to do things, the investigators, it's just too much work for them. So that's one of the things that I ask Steve if he is willing to let us figure out how can we -- if people meet a certain criteria, that's why I'm now working on, which I might have by ASCO, a certain endpoint, you get certain risk reduction on the volume, you have at least this much Ki67 that you can stay on it and we can track you with ctDNA and you can stay on it for some period of time. I think that would be fantastic.

Let's talk about it in Chicago.

Yes.

Yes. What other -- so given that we're coming to the top of the hour, Laura, what other presentations will you have there that we ought to be on the lookout for?

So there -- we have several, but I would say that 2 that have rapid orals, one is the rilvegostomig plus, which is a bispecific antibody of TIGIT, PD-1 plus T-DXd in the neoadjuvant setting. And again, it's one of these things that in the immune group, it works very well. It doesn't work in the non-immune group. And you don't overall improve on the strategy. So if you give it and then have to go to taxol and AC, you can get that same response if you just do taxol and AC. But of the people who get it and the people get their PCR, you can avoid standard chemotherapy and over half of them and avoid AC in almost everyone. That's again how we have to be thinking that, that is a victory, right? There are many things, but again, no benefit for these endocrine-driven Luminal B or Luminal A tumors. And we've got to do something about them. Now another study, our WISDOM study, this is where we showed our personalized screening versus annual screening and how much -- it actually -- not only did we not have a bunch of people show up with big cancers, we actually reduced the Stage IIb cancers by 1/3. So we presented this at San Antonio, and that was in JAMA in December. But now -- so there's a European personalized trial where they're not doing the pathogenic variants looking for pathogenic variants. And so they said, "Well, how much difference do you think that makes?" And I said, "Oh, I think it makes a lot of difference." And so we went back and looked, and it turns out that of the 716 patients, there are like something like 620 patients who had mutations that people had no idea they had. 30% of them had no family history. And...

These are somatic mutations? Or there's germline...

Yes. So BRCA1 , BRCA2. These are all -- no, no. These are all germline mutations.

All germline.

And it turns out that less than -- about 1% of them would have gotten high-risk screening if we didn't know about it. Again, this is my whole philosophy. It's like there is a test that is cheaper than mammogram for you to find out who is in that high-risk group. For goodness sakes, let's make sure that we get those people into screening in a more intensive way, and we can find those for the women in their 30s, so they don't get breast cancer in their 30s. And this is, again, stratify people by risk, stratify them by what they're at risk for, figure out how to do prevention, and to move that forward. That's -- and I want to just close by saying we have this meeting called RISE UP. So we're trying to revolutionize investigations to step up prevention for breast cancer. And so I talked Steven to looking to this, and he actually just got an impact award from the meeting because he came up with a way to use endoxifen as part of a contraception alternative. Can you imagine if we have -- we're trying to think about what are all the times that we already intervene in the course of a woman's life with hormones. Instead of just waiting for cancer to develop, what if we took a fresh look at how we are developing things like contraception or treatments for fibroids or treatments for the many common things that we have and made them risk reducing? So instead of 360,000 cancers a year, we might have 150,000. How fantastic would that be? And that's why I love working with Steve because he's like all open to great ideas and innovation that really make a difference for women.

Well, that's a great note to wrap up on now that we're just a minute past the top of the hour. Laura, always a pleasure and always insightful. We always learn something when we speak with you that we didn't know before. Steve, thanks for joining and contributing in the appropriate way. And we're hoping to see good things coming up down the road for endoxifen. Many of us that are listening and talking here will be at ASCO. So Laura, we'll look forward to seeing you in your presentations.

Great. Thanks so much.

Thank you for taking the time.

Thanks, everybody. Thanks, Mike.

Have a good night. All right. Talk to you soon, guys. Take care.