Atossa's lead program, (Z)-endoxifen, and its role in benefiting patients with breast cancer. Also, on the call with me will be Steven Quay, who's Founder, Chairman, CEO, and President of Atossa. He will not be making any formal remarks, but if we need his, if we need him to jump in, then we would be delighted to have him join us as well. Laura, thank-
I will jump in and just say thank you, Mike.
Okay.
Thank you, Dr. Esserman.
Yeah, please do. Yes
For doing this. 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? Yeah, 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, s uccess.
Well, I'm joined from my computer. Let me figure out how to get off this. I have a new. Okay. I have a new tool in my office. It 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 it didn't register me.
Well, now we see you, and now we hear you, so we are greatly relieved. Thank you for joining us, Laura. I so sorry for the informality, Dr. Esserman. I've, you know.
No, it's fine.
We've bonded so well over the last, I guess two years' time. Let me do an introduction so we can dive into the heart of the matter. 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 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 MBA from Stanford Business School. 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.
It's a combination that's rare. 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 trials, 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. 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, and in fact, I was telling this 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. Had to wait 10-minutes or 15- minutes for it was well worth it. If that gives you some of the, idea of the depth of her character, I think that, is a good summary of that. 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 your medical and scientific training, and you've built probably the most recognized breast cancer program in the world at UCSF. 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?
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. Like David Dilts 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 was the group I was part of, had the shortest number, but it was 336. People sort of thought that was funny. They had a, they had assembled all of the steps in, like, a series of poster boards across the, across a huge room. You know, that's not where we should be spending our time.
I think then 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. 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.
You know, the pace of change, like just for example, I'll get to the idea second, but just, you know, this idea of how many steps it gets to open things up, how long it takes to get your first patient enrolling in a, in a trial that just is open. It's kind of ridiculous the fact that every IRB had to be used. I thought, okay, what we need to do is develop a platform trial. You have one trial, and 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's all the semiconductor industries did.
You know, 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? That's really how I-SPY started. 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. Every experience or every piece of information adds to your understanding. We started with a Bayesian Adaptive Trial. At the time I was working with Donald Berry and-
Okay
Trying to work with figuring out how you can learn as a trial proceeded. That's how I-SPY was developed. What we did was we took high-risk women with stage II and III breast cancer and said, okay, breast cancer's not one disease, but we still treat it as one. How can we say let's profile them in different ways? Take, you know, say that we're gonna define the heterogeneity from the get-go, and we're gonna look in the different subsets, and we're gonna see how different people respond. We're gonna do everything up front before someone goes to the OR. 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.
Really what you want is an early indicator that something is working. Again, learn in 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 five years to find out how it works. That seemed enormously inefficient to me.
Right.
The order of therapy didn't matter, you could switch it up and say, okay, let's do it that way. If you do it that way, you can have drugs come in and out. We eventually over time have gotten a central IRB. 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 three weeks to the IRB approval and simultaneously four weeks for the FDA. In a month we have that arm of the trial enrolling in 48 sites at full tilt.
We're currently putting 500+ patients on one year. 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. 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. We're working on improving those endpoints so the FDA will have an acceptable early endpoint.
Right.
That our knowledge turns are three years and not 17. Now we're trying to do the same thing in that endocrine space, and we're gonna try and go backwards into that to try and figure out what is the right goal for what we want to see it change. Most women will do okay with endocrine therapy, but a certain number of people will not. 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 with Atossa because endoxifen is so incredibly well-tolerated. This really matters to women. You know, you've got a drugs that are standard of care that after three years 60% of women stop taking.
That should tell you something, we need to work harder to find things that are not only more effective but more tolerable. I would say that the sine qua non of what we're trying to do is get the right drugs to the right people at the right time and to have early endpoint that continuously guide how we learn and how fast we can move, we're trying to put a lot of pressure on the FDA to really move forward at that pace. You know, they want to test A versus B in the old way, that's actually not what women need. That's not what the field needs. As an independent, I'm on no advisory boards. I don't take so much as I don't, you know, take anything from any client, and I, that's not why I do things because I'm here as an advocate for my patients.
Yeah
For the 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.
Maybe that's a good point, if we could just maybe take a quick step back. 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. It sounded to me like, it sounds to me like I-SPY was the original protocol concept, you know, using some of Donald Berry's Bayesian statistics, and then Quantum Leap was created, or were Quantum Leap-
Oh.
I-SPY created at the same time?
Quantum, we started with the Foundation for the NIH. I was working in the cooperative groups. That's where I-SPY 1 had been done, and I had this idea that by starting with MRI, I worked with Nola Hylton, who was a physicist who developed the sequences for what became breast MRI, and that's how They said, 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. Then 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. Saying that everyone should be treated the same way is clearly wrong.
Right.
We needed a framework for that. I tried to set up through the 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 years to get it approved.
Wow.
I was just furious. I think-
I would imagine there's a lot of turf battles that happened over that.
Well, it's just like-
Kind of time.
There was like, it was just lost. The whole idea is like, once you've got the engine running, the whole idea is to keep it running.
Right. Right.
When people get distracted and do something else, that's when things fail. They told me I had to learn to wait my turn, I said, well, that's not gonna ever happen. I decided.
They don't know me very well, do they?
Exactly. I went to Anna Barker, who was then Deputy Director of the NCI.
Yep.
I'd asked Jorge Gomez, because this came out of the Specialized Programs of Research Excellence, the SPOREs. I said, who's the most innovative person at the NCI? He said, Anna Barker. I went to Anna. I said, we have this idea. I brought Don in. Then we started this protocol. She said, well, let's put it through the Foundation for the NIH, the Biomarkers Consortium, which we did. The minute Anna left the NCI, everyone said, well, because they thought it was too risky, because we started before we had all the money we thought we needed to run the trial. 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.
Right.
Clearly not true, since we've had 35 of them. They told me, well, that's it. It was a great success. You're done. I'm like, no. No. No. We're just getting started. 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. You know, people gather information and they bury it in notes, and it's not in an organized, structured form that can be easily exchanged and work for quality improvement, registries, trials, and care. The care was just as important as all these other things to be good and high quality. We were working on tools for that, and the board said that they wanted to do something more important.
I said, well, how about becoming the sponsor for I-SPY? They said, okay, great. That's how that started. That was, like, in 2013, end of 2013.
Yeah.
One of the things that's great is, you know, 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 turns and strategy and efficiency and management as a science? What is the science of management? You know, where is there all this white space that you can compress and you can work on trying to make the process better? That's a lot of what we've been doing.
Okay.
One of the first tools that we have, which is where you can take information directly from the EHR and have it go directly to the, you know, to the care. 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.
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 believe.
All right. I got to correct that. All right. Sorry. Thank you for correcting me. Sorry, I lost my place. You know, 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 for HER2+ and Triple-Negative Breast Cancer, but this ER+, HER2-negative luminal subtype has historically been the hardest nut to crack.
Absolutely.
In the neoadjuvant setting, with PCR rates that are pretty low. 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?
I think that, you know, over the course of these 10 years, I would say that we, you know, we have screened almost 6,000 patients, and the enrollment now it's up at about 3,800 patients that have gone through both I-SPY 2 and now 2.2. In 2022, in July of 2022, we changed the trial format to be something that we 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.
We then said, well, I want to bring the new agents up front and give novel therapies to patients before chemo, because the whole point of these novel therapies is to replace more toxic standard chemotherapy.
Right.
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 up front, you can actually cure somebody. You can prevent metastatic disease. We give 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. Then you get the best treatment based on your subtype. If you still don't have a good response, then you go to the last block of therapy, which has docetaxel. There's two really important places that we're trying to change.
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, and this is as defined by expression profiling, but importantly, you know, we're understanding so that a lot of these are the proximities of certain types of cells to the certain tumor cells or dendritic cells. Those are patients where we can really get pretty good responses, and we can probably replace a lot of standard chemotherapy. Antibody drug conjugates can combined with immune therapies. 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. We don't know that we can routinely do that. It turns out that the luminal B patients, either high-risk ER-positive tumors that don't respond to the immunotherapy, they don't really have a good response to chemotherapy either. That's true for the-
There are no targets. Are there any targets there for the immune system or not?
Well, there's estrogen receptor, progesterone receptor. I think we should be thinking about things like testosterone or androgen receptors as well. Combining, you know, the endocrine system is actually very, very complicated as well.
Yeah.
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, you know, where you can make these interesting combinations. 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 gonna help them, notwithstanding we still give it, but where we said, okay, we're gonna do six 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.
You know, 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. The 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%. We've almost tripled the chance that we can make a tumor go away, but that's largely driven by these immune subtypes. Our goal was to get 90% of patients to a complete response, and we're not gonna get there unless, you know, we do something about these luminal- B cancers.
Okay.
We have to make a change. Excuse me. I think that one of the things that Sorry.
Bless you.
Bad pollen day?
It is, like all over.
Yeah, I feel your pain.
It's warm. Yeah. That, sorry, we have to really think differently about how we're going to go after these tumors. I think the important thing for me is not only having something that's effective, but having something that is less toxic.
Yeah.
You know? It's really, really important. I think in the endocrine field, our standard therapies actually are pretty hard on women.
Yeah.
The aromatase inhibitors cause a ton of joint pain. At three years, 60% of people stop taking them. We give all women, you know, who are young, we've shut their ovaries down. That is actually pretty tough on people. As one of my patients used to say, you know, yesterday I was 36, today I'm 80.
You're right, I have menopause. Right. Yeah. Well, we have.
Not menopause, but creaky bones.
That as well.
It's hard to do things at 86. People feel like, you know, they've lost their vitality and so on, so it's very hard. Looking for things that are effective and less toxic is hugely important.
Right. Well, the one molecule you didn't mention is tamoxifen, that's obviously one that, you know, creates a lot of, you know. Women are supposed to stay on it for five years, 10 years in some cases, that's really tough as well.
Well, 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 mg and smaller doses, which is really much more tolerable. You know, thanks to my colleagues at Mayo who had, you know, 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.
I always assumed that endoxifen would be just as toxic or more toxic than tamoxifen, it is not. It absolutely is not. I think it's clearly an effective strategy that is extremely well-tolerated by women.
Well, do you wanna 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.
Right.
Do you have, you know?
That was actually why I think Matthew Goetz really started on this 'cause he was worried that people had differing metabolism. The way in which he measured it was very complicated. It was really hard. He thought, "Well, why not just start with the money business and start with that.
Right.
I think what's interesting is that it turns out to be really extremely well-tolerated. Let's put my light on here. I think that I want to say one other thing. There's another trial that I run. I run two 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- the person who's very low risk doesn't need to start screening till 50, and the person who's at a very high risk needs to screen more frequently.
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 over-diagnosing things like stage 0 cancer. I also started a trial called RECAST DCIS. It's all about reevaluating conditions for active surveillance that would be suitable as therapy for stage 0 lesions.
Instead of doing surgery and radiation, I'm a surgeon, we should be using our tools wisely. If someone just has some risk factors, they should get endocrine risk reduction, not PCR driven and not surgery and not radiation. It turns out that, you know, we have a trial testing three different endocrine therapies. Endoxifen is one of them. Against the standard, most people are using baby TAM for that. I have actually a lot of experience in RECAST also because we have 40 or 50 patients now at UCSF on that trial.
I started this with a long time registry to sort of say, why are we operating on these people? Doing active surveillance and finding out, using MRI imaging is my calling card, is 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 risk.
Oh, okay.
You can bring that down. Imaging is a catalyst for learning and figuring out how you can change. Over time, we figured out how to write a protocol so that we could do appropriate management. One of the things that I'm impressed by is here purely, these are people who are purely given the, like endoxifen or Tam or whatever it is that they're given. I have experience with how people tolerate this, whether they're premenopausal or postmenopausal. I can tell you that endoxifen is extremely well-tolerated.
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 receptors, 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. 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, you know, people stay on it, that means they're tolerating the medicine and they don't feel like they need to get off it. They're not going to stay on it if it doesn't work to reduce, you know, the background on the MR. You know, if the lesions themselves aren't coming down.
The fact that people can stay on it and the trial works that you get six months of the treatment up front, 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. Someone that's, you know, that's the trials, the six-month period, that's the key endpoint. At that point, people have the options to stay on and skip surgery if they meet certain criteria. There is your measure of tolerability.
Someone who hates the endocrine therapy is going to say, Ugh, I'm not doing this. I want to have surgery. 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, you know, that's not, w e, you know, we can't analyze that data ahead of time. I think that in terms of, you know, for whatever reason, you know, 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.
What's the dose of baby tamoxifen?
5 mg.
5 mg versus-
Versus 20 mg. It's very interesting, you know, in the NSABP trial, which was the first big prevention trial, the P-1 trial that was reported in 1998, there were like 13,600 women on it. They were randomized to tamoxifen versus nothing for being high risk. You know, other than hot flashes, the same number of women quit on both arms.
Huh.
The tools that we used, which obviously weren't very good, showed that there really weren't side effects for particularly, but that's just not the experience that people have. People really just don't feel well on it. Even at the lower doses, it is much better, but it's not gone. 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. If you can get rid of it, how fantastic that is. I mean, you know, 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.
Right
Of the Triple-Negative
Most investors don't realize that because, you know, 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, you know, the other ones, the HER2 and the Triple Negatives, we're figuring out how to cure.
Yeah.
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. How fantastic if we could do that without making people sick.
Right.
Especially if you have-
If I could just interrupt, Laura.
Yeah.
I mean, to me, I finally realized 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-
The one, right.
I think it's one of those others that's causing the mischief.
Obviously, it's like I kept saying, I'm saying, wow, what is the magic here? Why is this not causing side effects? I was thinking, oh, if this is the active ingredient, it's really, people are gonna have more hot flashes, really feel terrible, but they don't. To me, like, a drug, so I think one other thing 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.
Right.
I think we have to think about this opportunity to do better. I mean, isn't that what it's all about?
The tolerability has got to be a factor, but you can't sacrifice efficacy for that. I mean, it's a, you know, obvious statement, but, you know.
Well, you gotta think about, there are some surrogates, like drop in Ki-67.
Well, I was just gonna ask, yeah.
You can look at the background enhancement of 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, you know, the 20 years to really prove it, you know, we'll all be dead.
You know, 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 these, for the lowest of the lowest risk of the I-SPY 2 patients, you know, people who have that low, those luminal B cancers. I'm working on trying to come up with an endpoint. I mean, it'll take time and, you know, the FDA's not gonna like it at first, but I think it's something that we can do and we can come up with.
We must really work towards saying we need early markers of effectiveness. We need early markers of measurements of tolerability. We measure lots of tolerability in lots of ways, including a tool called the FACT-GP5, which says how bothered are you by symptoms today, 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?
Right.
I think that's super important.
Can we tether this to some data? You did present the I-SPY 2 endocrine optimization pilot at San Antonio, where you were 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 Ki-67?
Yeah
MR functional tumor.
We actually haven't presented the elagolix study yet. That is something that I am super excited about, and I have to say kudos to Steven for agreeing to this combination that we, you know, we were trying to give endoxifen at higher doses with abemaciclib, which is a CDK4/6 inhibitor. We had seen the spike in estradiol, which can lead to cysts, and it's true. Everyone was saying, well, you have to give ovarian suppression. I said, well, I'm not ready to give up yet. I contacted Hugh Taylor, who's the chair of OBGYN at Yale, who I had met through the work I was doing on this Rise Up conference, which we're going to come back to.
He said, oh, well, that's because, you know, 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. He said, and I said, well, Hugh, isn't there a better way? Isn't there another way that we could do this without, you know, causing full ovarian suppression, which is so hard on women? He said, oh, yes, absolutely. I've done all this work with elagolix, which is an antagonist that you can, you know, that it's partial, so you can give half the dose. Obviously, this is not presented data. We haven't, you know, finished it. We did 10 patients each, and I called up Steve and I said, we've got this idea, w hat do you think? He said, great, let's do it.
Yeah.
He did it like this. We got an amendment in. We had it in two weeks we were testing it.
Oh, wow.
What's so exciting is that, we are seeing the same drop in the cell turnover, the same drop in functional tumor volume. The FACT-GP5, that how bothered are you by symptoms, is so much better in women who are on the elagolix versus the ovarian suppression. I, to me, that's a huge win. I would really love to expand this. 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?
I love you, Laura, but I have to say we're a public company here, and so all these comments are subject to.
Right, right. Sorry
SEC and everybody else. Right.
It's fine. We'll just put that.
Sorry. Sorry about that. You can cut that out.
it's okay.
I'm just very frustrated.
Let's set that aside for a time being.
Like AbbVie says, oh, because we want AbbVie to help, and heard from Dr. Taylor is that they're not. I mean, I think women's health, the real innovative work in women's health is not going forward as it should.
It's just not.
Yeah.
It's hard to get people interested in it.
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 promise in that combination, or is that?
Well, absolutely. I think, you know, I think.
I mean, really the side effects from that really come from the abemaciclib, which causes diarrhea and can cause.
Right.
There's no added toxicity whatsoever, and the combination appears to work just as well. How we can measure, you know, 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. One of the things that's very frustrating to me when I see people looking at the selective estrogen receptor degraders, everyone's sticking with the old model of the adjuvant therapy. 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, these trials are, like, a billion dollar to show the difference between an AI and a SERD.
Right
They take a long time. That just feels to me like not the most efficient way to move the field forward.
What's the best patient population in which to use a combination with abemaciclib, and what is the early endpoint that you would seek? Is it Ki-67 or something else?
Well, I think it's gonna have to be a combination of endpoints. I would say that, you know, where I think people who have small, little tumors, you know, what you should just do is a tolerability study, and again, to show, you know, that the drugs are more tolerable. I, you know, I don't know. I think that because this is an active metabolite of tamoxifen, you know, there may be, you know, maybe we should be thinking about showing equivalency so that you can get it on the market so you can do more things, more quickly, with combinations. I think that when you have people with more, you know, so with more burden of disease, so Stage II and III early stage cancer, there you want to try and give the therapy upfront.
Again, we do everything in the neoadjuvant setting to try and measure those impacts so we can see, yes, the cell turnover rate comes down, and there's, you know, a good, you know, there's a big body of literature that shows that if you can bring the cell turnover rate to below 10%, that really should be, that's the predictor of outcome. That was the POETIC study, and that was, you know, based on a neoadjuvant cohort within the ATAC, the comparison of an aromatase inhibitor to tamoxifen, so, and the combination. They showed superiority, slight superiority of the aromatase inhibitor compared to tamoxifen, and that felt, with Ki-67.
Turns out that, you know, in this case, endoxifen, 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, you know, just had stopped her hormone therapy because it was just, you know, she just couldn't move her hand. She couldn't do anything, and it was so difficult.
She had, you know, a recurrence with DCIS, which, you know, okay, that's not gonna kill her, but she had had a very bad cancer in the past, so we wanted to, you know, put her back on it. We finally have her on at, like, a lower dose of, you know, exemestane, which she's tolerating okay. It would be great to be able to give her a drug like this that she's going to tolerate better. 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, you know, 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. Obviously, this would be a great benefit to women with breast cancer if it were on the market quickly. You're doing, you know, 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?
It would I think.
Conceive of the fastest path through that regulatory, you know, system to get this drug to patients as, you know, 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.
Yeah.
We have to. Okay? I think everybody who has any influence anywhere, you know, it's really important.
Yeah
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, whatever you say that you're going to achieve, that when you come back with the data in hand.
Right
They say yes. I mean, that's gonna be, I think we just need to reestablish integrity and the ability of non-interference in the Food and Drug Administration's ability to regulate the drug industry. I think that, you know, we are working very hard with the Oncology Center of Excellence to show that you can look at, you know, I've myself and my, 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. Even in the high-risk setting, we've used, you know, complete response, PCR, as that early endpoint.
Right.
FDA has not leaned in enough on that. Why is that? 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. If you have a 0 versus everybody else, that's probably not the right cut point. If you think that there's a whole, you know, from 0 all the way to 3 or 4, the cut point is probably somewhere around 1 or 1 and 2. For hormone positive cancers, it's more like 2. For HER2, it's 1.1. 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 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. 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.
Right
You have to be able to say that if drug A versus drug B is different. What you need to do is find the cut point, not for all patients, but for the subtype of cancer that is more homogenous. The HER2s are different. Even the luminal versus non-luminal HER2s are very different. In the hormone positive, it's whether you're immune or not, but the majority are non-immune.
Right.
That threshold's a little bit different, so that's two. 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. 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 eight years with metastatic disease, where you really are not going to be able to cure them.
Right. Just to be clear, these patients are not expected to go to surgery though, right? These are gonna be like biomarkers like Ki-67.
No, no. They could go to-
Okay
Like at six months.
To go to surgery?
They go to, yeah, because residual cancer-
Yeah. Okay, you get pCR could be an endpoint.
is under measure at surgery.
Okay.
You have to give yourself a window of time for the endocrine therapy to work.
Right.
Same thing for the chemotherapy, whatever. The idea is, think about it this way. You've got a patient who's got treatment over a five-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. We, by the way, do it with MRI along the way, and then use that indicator to predict what happens out here. That's what is going to, you know, that's what's gonna accelerate knowledge turns. You know, that's actually one of the things that Andy Grove wrote this amazing piece in JAMA in 2007 after he got prostate cancer.
He was founder and one of the Chief Executive Officers of Intel, and he said, wow, a view of the out. This is sort of looking at healthcare, a view from the outside. It's a scathing 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 doomed to having really long knowledge turns, which he's completely right about.
Right.
I knew him well, actually. He used to call I-SPY the loop-de-loop trial. I was actually working with, before he got super sick, we were working on something for Parkinson's for him. It was, you know, it's this idea that really was where I really did get the idea from I-SPY for looking at his philosophies. Like, I never put a product on the market without having the second, third, and fourth version of it.
Yeah.
They set up a system where they could constantly test and constantly improve, and that's what's changed the software industry.
Right.
It's of this huge learning engine.
I'm trying to do that in medicine. Breast cancer is a perfect place to do it in. You know, 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 treatments.
Right. Right.
Laura, Andy was an investor.
Yeah
The gadolinium drug that I invented for the MRI imaging.
Huh.
Oh, is that right?
It's kind of a full circle, yeah.
Yeah, he's.
Big fan.
What a character. Yeah.
He was a big benefactor of the Prostate Cancer Foundation when he was alive as well.
Yeah
Attended all the scientific retreats.
Yeah-
But, uh-
He could be very tough.
Can the FDA, you know, deal with a loop-de-loop trial? I mean, again, where does it enter that, the process where, you know, somebody, you know CDER Oncology Center of Excellence signs their name on it and says, this is now gonna be available to patients based on the trial results?
I think the FDA still likes a traditional trial of A versus B. I obviously don't think that's the best thing, but, you know, I think what we're trying to do right now, I-SPY 2 is a signal-finding trial. When we find a signal, what we wanna 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. You know, the, I think that where we are, where we don't necessarily agree is, you know, they're like, well, you know, people can get whatever adjuvant therapy they want afterwards. If you don't, if you have a great response, people aren't gonna give adjuvant therapy afterwards.
If you don't have a good response, of course you're gonna get more therapy. That's the same thing with progression-free survival in the metastatic setting. When someone progresses, people don't say, oh, I'm sorry. I can't treat you. You're on a clinical trial. I mean, that would be unethical.
Right.
Why is that any different? 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 three years or five years, whatever it is.
Right.
I will now give accelerated approval.
Right. you know.
That's the goal.
The nice thing about, the great thing about I-SPY is that you're not looking for, you know, low, you know, a low signal. You're looking for a big signal that.
Looking for a big signal.
Yeah.
Again, I think that we can be conveners. You know, we are 48 sites. We have 200 investigators. We've worked with 35 companies.
Yeah.
You know, I think what Richard Pazdur told me when he was there.
Well, he may come back. Well, that seems to be the odds.
He might come back. He might come back.
I think it's on the on the Polymarket as the next head of CDER.
Is the prediction good that he'll come back?
Right. Yeah. That's what I'm hearing.
Well, he, you know, he'll want some guarantee of scientific independence, I'm sure.
Yes, I'm sure.
What he said was, okay, bring the community along with you, and if you can bring the community along with you, we're gonna look very seriously at it." That's what we're doing. We're bringing all the advocates. We're bringing, you know, all the companies, and we're trying to speak as a voice to say, t his 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. That's not what I'm about. I'm about being a catalyst for change, good change, you know, 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.
Yeah.
To figure out who needs them, so we don't over-treat and we don't under-treat.
Yeah.
That's the goal. I think, you know, the field needs people like us, who are the leaders of I-SPY.
Well, I'd say we should clone you across-.
Yeah
you know, 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 gonna be very highly replicable.
Yeah. Steve, did you have.
Laura, I mean, with the.
We'll do that.
The day I got an email from a woman that was in your trial, you know, in our trial, yeah, in endoxifen trial, said, my tumor shrank by 78% and I won the half-marathon in my age group.
Oh my gosh.
That was a good day.
Amazing.
Yeah, you know, the thing is these people wanna stay on the drug after six months. You know, here's the problem. For a drug that's not approved to be able, you 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. That's one of the things that I asked Steve if he's willing to let us figure out how can we, if people meet a certain criteria, that's what 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 p63, then 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.
Uh-
Let's talk about it in Chicago.
Yeah.
Yeah. What other, 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?
There are, we have several, but I would say the two that have rapid orals, one is the rilvegostomig plus, which is the bispecific antibody of TIGIT PD-1.
Right
plus T-DXd in the neo-adjuvant setting.
Oh, okay.
It's
Nice.
You know, 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. You don't overall improve on the strategy. 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. Of the people who get it and the people who get their PCR, you can avoid standard chemotherapy in 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?
Yeah. Yeah.
There are many things, again, no benefit for these endocrine-driven luminal B or luminal A tumors, and we, you know, we've got to do something about them. Another study, our Wisdom Study, this is where we showed our personalized screening versus, you know, annual screening. You know, it actually not only did we not have a bunch of people show up with big cancers, we actually reduced the Stage II-B cancers by a third. We presented this at San Antonio, and that was in JAMA in December. There's a European personalized trial where they're not doing the pathogenic variants, looking for pathogenic variants.
They said, w ell, how much difference do you think that makes? I said, oh, I think it makes a lot of difference. We went back and looked, and it turns out that of the 716 patients, there were something like 620 patients who had mutations that people had no idea they had.
Wow.
30% of them had no family history.
These were somatic mutations?
Yeah.
Were they germline too?
BRCA1, BRCA2.
Okay.
These are all germline mutations.
All germline. Okay.
It turns out that less than about 1% of them would've gotten high-risk screening if we didn't know about it. I, again, this is my whole philosophy, is like there is a test that is cheaper than a 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.
Yeah.
This is again, stratify people by risk. Stratify them by what they're at risk for. Figure out how to do prevention, and so move that forward. That's and I wanna just close by saying we have this meeting called Rise Up. We're trying to revolutionize investigations to step up prevention for breast cancer. You know, I talked Steve into 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.
Oh, right.
I mean, can you imagine if we have, you know, 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 re-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.
Yeah.
Instead of 360,000 cancers a year, we might have 150,000. How fantastic would that be? That's why I love working with Steve, 'cause he's, like, all open to great ideas.
All right.
that would 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. Always learn something when we speak with you that we didn't know before. Steve, thanks for joining and contributing in the appropriate way. We're hoping, you know, 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 and your presentations.
Great. Thanks so much.
Thanks so much for taking the time.
Thanks, everybody. Safe travels.
Okay.
All right, have a good night. All right, talk to you soon, guys. Take care.