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Joseph Kim:
Welcome to Clinical Research Confidential. On this show, we highlight and demystify the inner workings of this greatly misunderstood activity called clinical research. Now, why is clinical research important? Well, it’s the basis for nearly every modern remedy for sickness and a growing method to build trust and solutions meant to optimize health, but it’s not for the faint of heart. And so, on this show, you’ll hear what it really takes to succeed in the clinical research game. I’m your host, Joseph Kim, and I’ve spent over 23 years in the clinical research industry, now serving as the chief strategy officer for ProofPilot. Get ready for some adventures as we look into the underbelly of clinical research.

Joseph Kim:
And today, I’m here with Dr. Stacy Blain, who’s the co-founder, chief scientific officer, and CEO of CONCARLO Therapeutics, which is a really exciting oncology pharmaceutical company that’s doing a lot of research that hasn’t yet hit the clinic, that is, hasn’t been tested in humans yet. Stacy, welcome to the show.

Stacy Blain:
Thank you. Happy to be here.

Joseph Kim:
In this show, we talk a lot about the sausage-making of research, but what I think most people don’t fully appreciate is like, before research happens in humans, it happens in the lab, it happens in animals, and all this preclinical work is still a bit of a mystery to most. I haven’t focused on it in a great deal of my career. I’ve spent 23 years in clinical research, so it’s still kind of a mystery to me. So we’re going to dive into that. But before we go there, I’d love to talk about your personal history, how you got into clinical research and ended up as the CEO and chief scientific officer of a biotech, which is kind of a far journey from bench science, which is, you know, you started out as a molecular biologist. Tell us that story.

Stacy Blain:
So I had always wanted to be a scientist. I think like a lot of scientists, it was sort of in your DNA as a kid. So I got my PhD. I studied HIV in the early 90s, which was a really seminal time. HIV was really sort of a hot topic, and I think I learned really early on that what we did in the lab could quickly translate into the clinic because we were studying the proteins, reverse transcriptase, and integrase that eventually were drugged and are still the medicines that help control that disease for millions of people. So that was sort of my first experience that, you know, wow, what we do here really can move very quickly into people. I then went to Sloan-Kettering and worked for a really brilliant man, John Massagué, he’s the head of the SKI institute. It was a really intense experience. There were like 15 postdoctoral fellows. Everyone was brilliant. We were all like in the stew, working hard all the time, thinking all the time. I mean, it was just like, you could see the little sparks flying out of people’s brains and hitting other people’s brains. And I joined right after he had discovered this protein called p27, and I was essentially like the first person in to work on p27. The woman who had discovered it, she was moving on, and I picked up the baton and essentially never put it down. Have continued working on that protein literally for 30 years. And eventually left Sloan-Kettering. I started my own lab, which was the journey that all PhD scientists wanted to do, right? We were, let’s work hard, and eventually, we’ll have our own gig, and we’ll become a professor. And I went to one of the state universities of New York in Brooklyn, the downstate campus, and I had an additional desire, which was I wanted to be with a lot of students after being in that Uber professional environment in Sloan Kettering, I wanted to go back a little bit to my roots that I’d seen at Columbia and be with students and teach in the classroom and have students in my lab and really sort of try to work with that younger generation, and that was one of my goals, so that is why I went to the state university, and literally continued working on p27 the entire time. Now I should pause and say p27 happens to be a really important protein. I don’t think we knew when we discovered it like exactly was going to be, hindsight’s always 2020, but p27 controls is the natural inhibitor of the three main drivers of all cell proliferation and all cancer proliferation, and all drug resistance. So CDK4, CDK6, and CDK2 are sort of the Holy Grail targets in oncology. If we can effectively drug those proteins specifically in tumor cells and not in normal cells, that’s the transformative potential. So p27 is the inhibitor, that’s the way nature normally inhibits those proteins. So I continued working on p27 and thus CDK4, 6, and 2, and was really content, you know, was like struggling writing grants and publishing papers and training students is a lot harder than I thought it was. I mean, in full disclosure, right? You know, not every student had the same aspirations that I had, which is to become a professor. So had to navigate with students who maybe were just like science, and they realized they didn’t like it enough to stay in science, but we still had to keep them in science. So had the normal struggles, but essentially around 2010, we discovered the way p27 turned these three important kinases on and off.

Joseph Kim:
So before you go into there, how are you doing your research? Just in test tubes, in animals, like, because this is all not in humans at this point, right?

Stacy Blain:
No, no, we are fully, literally, like we’re at the bench. We are wearing white coats, wearing gloves, doing things in tissue culture cells, so human cells grow in plastic dishes. We’re doing a lot of biochemical assays, so those are purified proteins in little test tubes, and doing things with them, and some animals. We are testing in genetically modified animals. We are testing our drugs, and it’s not even a drug, we’re testing our hypotheses. So it’s really all lab-based, and lab-based is very hypothesis-driven. We have a hypothesis. We think X, let’s test it. Sometimes we are right, and then we would develop Y, sometimes, we were wrong, and we’d have to go back and create a new hypothesis. So very much basic science for the purpose of just understanding. And I always say, I wanted to know where p27 was in the cell, who it was talking to, what it was wearing, and you know what, it might be going next. That was really my modus operandi. Like I just was so focused on understanding that protein. But when you focus entirely on one protein, you learn a lot of things about it, and we learned how it turned CDK4, 6, on and off, and that was really important, and then we patented that, as you do when you make a discovery and when you work at a university that has a really robust tech transfer, they say, oh, this is new intellectual property, we should patent it. So we did, and then, literally, three things happened that were a little bit of serendipity, I think, right? That they all had to happen sort of at the same time. I wrote a big grant to the NIH, which is the major funder for basic biomedical research, and the grant got trashed. It didn’t get funded. And I was like, I don’t understand this. So I called my program officer, and I said, this is a great grant, Like, what’s going on? And he said, we agree, this is a great grant, but in … 3 you’re describing you want to make a drug to harness this ability of p27 to turn CDK4, 6, on and off, and you’re an academic. You can’t make drugs in academia, you just will never get the investment. It’s too hard a process. If you want to create a drug, you need to start a company, and you need to get SBIR funding, which is a portion of the government budget that funds small biotech companies to try to translate research into human use. So I said, okay, that wasn’t my plan. I’m an academic. I’m supposed to just stay here and do academia for the rest of my life. And the next thing that happened was the tech transfer office said, oh, this is a really interesting idea, let’s go on a sort of a dog and pony show and talk to some venture capitalists to see if they’re interested in this idea. And I naively thought, oh, great, they’re going to be so interested, they’re going to give me all this money, and I’m going to continue working on this in my laboratory. Well, what would have happened is they would have probably bought the idea away, and it would have gone somewhere else, and someone else would have done that, and it really was not ready for prime time. A lot of it still existed in my head, it was really just a concept, honestly. It was like a piece of paper about how we could … So I think the venture capitalists realized that, so they passed. But I was sort of like, why would I give this away? Like, if we’re going to start a company, maybe I should listen to the NIH. And so the last thing that happened was I applied really on a whim to a great program at the New York City Economic Development Corporation, which was a program that if you had a small company, they would help you write an SBIR grant, and I got awarded this grant from the NYC EDC. And so suddenly all these sort of forces in the universe were saying, you should start this company. And then I’d say the other fortuitous part is my husband is sort of a venture capitalist, serial entrepreneur, and really knew how to start companies, knew how to raise money, so that was one. One of my really good friends was sort of a fractional COO, so she knew how to start companies, she knew how to do things that I had no idea how to do, like payroll, insurance, how to pay electric bills for a company. Like I didn’t know what a cap table was, so didn’t have those skills, couldn’t have done it on my own. And then the last fortuitous well, there’s two last things, is we had an incubator for small companies at Downstate. So literally, you could just rent space across the street at the same place where I worked every day. And then the last thing was I had a talented graduate student who was graduating, he didn’t want to go to academia, which sort of completely surprised me. I was like, Why would you not want to have my life? He wanted to work at a company, and so suddenly, I had someone to work at the company. So all these things happened, and we started the company, and we raised some money, literally bootstrapped from friends, family, put in founders money. The NYC EDC helped us get the SBIR award, and suddenly, we had this company. And it wasn’t really in my plans, but I think sometimes karma sort of shows you what you’re supposed to do, which was, I had been from my earliest days as a graduate student, thinking about translating my work into humans. I had written about it as early as 2003. In my first grant that I’d ever written, I said, If this happens, this could be a drug. And then I had written to the NIH about a drug, so it was like I knew it, but I couldn’t see it, and so thank goodness that the universe sort of pushed me to do it, because this is really, now that I’m doing it, this is what I was gunning for the whole time since I started working as … 95, was like harness the potential of the lab and working in the lab. What we do in the lab should and can translate into changes, drugs for humans.

Joseph Kim:
Amazing story. I mean, in a nutshell, you started your education and career focusing on the business of science, and then as you start to discover things, you’re like, wow, I have to actually go into the science business, which is two different things, right? And so I know you’ve struggled a little bit, sort of emotionally like, wow, I didn’t want to be this, I always wanted to be a pure scientist. But now you’re going for some real-world application and trying to bring something to test it and bring it to market. How has that changed just your overall approach to science, meaning, like in the early days, like you said, you just want to learn everything you want to know about this one protein, but now it’s a little bit different. It’s not just about learning everything you want to know. You have to focus that on something that’s going to deliver an outcome. Tell me about that mind shift.

Stacy Blain:
So we started the company, which is called CONCARLO Therapeutics, and I think even the name sort of changed, you know, reflects my mind shift. So I have three children, Connor, Carly, and Logan, so the name is an amalgamation of their three names, which is sort of what I was thinking, right? Like I had been teaching the cancer block for a long time, I’m really versed in understanding the statistics and the treatment of cancer and the successes in that journey as a field, and the failures, and the limitations, and the work that we still have to do. So I was not only a bench scientist, but I was also a serious educator. You know, I have taught thousands and thousands of medical students, and medical students essentially don’t really want to know science when they start out, they’re like, why do I need to know this? I’m going to, like, treat patients, and you have to teach them and remind them like, literally, everything you use in the clinic comes from a scientist’s brain and a scientist’s hands and like a long struggle at the bench. So that became my personal sort of mission to teach medical students and clinicians. I did a lot of continuing medical education for the fellows at our university and the residents, and really sort of that was something really important to me. I also started doing a lot of translational research when I was this bench scientist. We needed human samples from actual human patients who were kind enough and generous, and brave enough during the course of their cancer journeys to donate their biopsy material, and we could actually then study that and use that in the clinic and grow that and learn from that. And so I started getting closer and closer to the patients and what they were going through by working with brilliant pathologists and oncologists and breast cancer surgeons. And it was really sort of this evolution of, we really should be getting our research out of the ivory tower. That was sort of what I was, have been really sort of where I’ve been sitting for the last five years, and have been sort of vocal about that. Like, look, we as scientists, we take money from philanthropic organizations like the American Cancer Society or the Susan G. Komen Foundation, and the NIH. That’s taxpayer money. Those people that are paying taxes are not as interested just to do science for science sake. They want researchers to do science for their sakes and to come up with cures for their maladies, and that is actually our responsibility. And I had always taken taxpayer money and philanthropic money very, very seriously, and I had expressed that to my graduate students. Like this money is very valuable. They are infusing these dollars with hope. They are depending on us to use these resources wisely and to come up with things that will actually help them. So, yes, I was a bench scientist learning about these things, but I had these threads running through my everyday thought and really was very honored to be a bench scientist to, you know, what an amazing job that I could literally think really, really hard and test things that came out of my brain and hope that they were working, and if they didn’t, then have the luxury to rethink hard again and change my hypothesis. So as I started the company, CONCARLO, and we really were like a scrap of paper at that time, and we had to do a lot of basic science, the big change is that that mindset that was always there became front and foremost that everything has to add value. It has to add value to our hypothesis to make a drug, and if it doesn’t add value, then we really shouldn’t be doing it. And so we started doing experiments that would sort of tailor to this hypothesis is now a drug. And so that was the big mindset, like we actually have a drug. It’s not just a hypothesis. Like if the drug this, then what has to happen? And the big thing that I didn’t realize, which has been so amazing, is that there’s a really a big wall, I think, in general between academic research and biotech, and there’s not a lot of cross-pollination, maybe now, more, it’s starting, but there are brilliant scientists that work in biotech and in pharma, and I had never had access to them. I just didn’t know them. All my colleagues were academics, and suddenly I was meeting these people that had sort of crossed over to the dark side and were now doing biotech research, and they had been amazing scientists in their life, and they continue to be amazing scientists, and they just were more focused on the human condition. And so we were still doing amazing science, it was just much more value-added than before. And the other thing that I realized, which has been, you know, it humbles me, is that it takes a lot of work. It takes so much more to develop a drug than to have an idea. You have to make the drug, and it has to be stable. It has to be made on equipment that can make it in kilogram quantities, right? It can’t be in a small scale, it’s got to be on special process equipment. It has to be made in clean rooms. It has to be made sterile. It has to be the same exact material batch to batch. We have to have commercialization, I mean how are you going to distribute? How much is it going to cost? How is it going to get to patients? How many times a week are we going to dose the patients? For what length of time? Patients don’t want to come in every day. So can you dose them less frequently? What’s the clinical trial going to look like? How are we going to recruit those patients? What prior conditions are they going to have? What prior treatments are they going to have? And I have met people that have now dedicated their entire careers to every single step of what I just described. So my career was at the beginning. It is the big visionary thinking to understand the science, the way p27 and CDK 4, 6, move around in a cell, how they interact, how they talk, what they do, and how can we harness that. But then I’ve been so fortunate to meet the people that literally can say, okay, I’m going to take that, and I’m going to figure out how to make it stable, how that drug is going to be sitting on a shelf for a year. That’s something that I would never have thought about, but that’s really important. Those expiration dates on the medicine, those are important, right? And so people have spent their career just doing that. We have people that do something called full finish, which is literally when the drug is finished, it comes off the machine, and it goes into the bottle or the tube. How does that happen? How is it stable? How does that work? And I’m in awe of them because that’s not a talent that I have, and I learn from them every single day. So biotech, now that I’m in this world, is honestly, for me, my learning curve is vertical again. And as a professor, it had sort of tapered off a little bit. Yes, we were doing big science, and we were doing big things, but it was really all sort of driven by that. Now it’s driven by all these external forces. And I will say it’s really hard, you know, it’s not easy to think that’s really stable. It’s not easy to you have to think about toxicity and what happens when you dose a dog or a rat. How is that going to translate into dosing a human? How is the dose going to translate? How are those side effects going to translate, and all of those things? And so my journey over the last, you know, since we started CONCARLO, almost six years ago now, has been recognizing that there is this whole other world that I knew nothing about, and it’s thrilling, and it’s close to patients, and it’s exciting, and it is full of brilliant people that have that same mission to bring good medicines, great medicines, to patients as quickly as we can. So that’s a long answer, but I think it was, the kernels were there, and it took some nudges, and now we still do amazing science in biotech. We still ask many of the same questions. We just ask them with a different lens, and the lens should be there, in my opinion, which is, does this add value to our drug and help us get this to our patients more rapidly?

Joseph Kim:
Yeah, well, I think it was a long answer, but it was important that you said it in the way you said it, I think, because few people understand that whole journey of a molecule and the many, many scientists and operations folks and business folks and manufacturing folks and quality folks who have to play a part and nobody’s working for free, and not to sort of defend pharma companies or US drug prices, but all that stuff is very expensive. So when people clamor about, well, this drug should be free, like, well, let’s look at everyone who’s involved in bringing that drug either to market or actually making it and making sure to your point, it’s stable, safe, clean, consistent. Let’s see who’s going to do that work for free. It’s just not possible. I don’t have the answer to that, but I love what you said because it highlights the complexity and expense, and smarts that it takes to do the science business, as I said. But let’s jump into your research now. Let’s talk about the molecule you’re developing. Tell us about the animal studies you’ve worked in. Let’s start there, and then I’ll move to sort of the application in humans.

Stacy Blain:
Sure, so we are a p27 company. We’re all in on p27 because we believe and think a lot of people in the field believe it as well that it is a transformative target, right? This is the way nature inhibits the three main drivers of cancer, all cancers, and drug resistance. And so drug resistance, what does that mean in 2022 or 2023, this era of precision oncology, I think most people have heard of that. And the concept of precision oncology is, if I can identify the particular perturbation that is driving your particular cancer, I can give you a drug to deal with that particular perturbation. And that has been the era we’ve been living in for the last four years, which has really been amazing and really changed outcomes for a lot of cancer patients, but we now sort of recognize a lot of those liabilities, which is cancer is rapidly evolving, and even though I put that blockade into your tumor, there’s lots of room in the pathways for evolution to happen. And so by that, I mean like if I block the tumor cell too high in sort of what I call the oncogenic funnel, that the pathway that’s driving that proliferation, if I block too high, let’s say at the cell surface or even in the middle, the squishy middle of the cell, there’s still a lot of room for evolution away from that drug that I put on. And that’s what happens, and that is now a very well-understood pathway. So that means, look, you really need to draw a drug at the bottom of the oncogenic funnel, right? The same way that it’s easier to block the flow of water by pinching off the really narrow bottom of the funnel than to try to stop the flow of water at the top, or the flow of water in the middle. That’s what we need to do. We need to drug at the bottom of that oncogenic funnel, and that, in combination with many of our other precision oncology drugs would make better therapies. We could prevent that drug resistance and/or deal with the resistance after it’s happened. So CDK 4 six and CDK 2 live at the bottom of the funnel. People are, you know, have drugs, the CDK 4 inhibitors. This is the Ibrance, the … of the world. We don’t have CDK 2 inhibitors that is really been virtually impossible to drug because it looks very similar to lots of other targets in the cell, and so all of our attempts to drug CDK 2 have hit other things and caused a lot of toxicity for our patients, so they haven’t made it to the clinic. So we said, what if we drug the other player that is frequently forgotten in that sort of ensemble of five proteins CDK 4, 6, and 2, their other interacting proteins Cyclin D in CDK and Cyclin E and p27. p27 lives there and it lives there as an on-off switch, and it turns these kinases on, or it turns them off. And that’s sort of my claim to fame is figuring out that that switch is a modification, sort of think about it, literally, as switch that goes up or switch that goes down. And so when p27 gets modified on, when p27 is not modified off, that’s what we discovered. And we said, well, what if we created drugs that blocked, that sort of froze, locked that switch in the off condition so that the CDKs were off? And that’s what we’ve done. And so our molecule, our lead compound is actually, again, we went back to nature because nature had already figured out how to do that. So p27 is the inhibitor of these three proteins. There’s another protein that inhibits p27 and tells p27 time to be off, and then it turns these proteins off. So we took that other protein which was called Alt, and we said that was our first generation inhibitor, and we did some animal studies and some studies in tissue culture cells that if you took Alt and put it into cells, it turned off, it got p27 to do its job, and it turned the proliferation of these cells off so they stopped growing. And it worked in drug-resistant cancer cells, it worked in treatment-naive cancer cells, it worked in pancreatic cancer cells, it worked in breast cancer cells, it worked in ovarian cells. It was really a great drug. It worked in cells that were resistant to many, many of the therapies that are given clinically, including Ibrance, which is approved for metastatic HR-positive breast cancer. But we know that there are roughly like 40,000 women annually, or men, breast cancer space, that become resistant to Ibrance every year, and we had cells from people like that, and it worked. So we were like, this is great. The other really interesting thing about Alt was, because it is the way the cell normally regulates p27 to regulate these three kinases, it was regulated itself. So when you put it in a non-ulcer cell, so a normal mammary cell or a normal intestinal cell, it sort of got degraded rather quickly, so it didn’t have the same effect in normal cells. So we had found a therapy that basically worked in tumor cells, and so we will focus on breast cancer and now in ovarian cancer. So it worked in all of these drug-resistant breast cancer cells, but in normal mammary cells, it didn’t cause the same phenotype. In the breast cancer cells, it killed those cells, it caused them to undergo this form of tumor cell death, which is what you want, you want to reduce the tumor volumes in patients. But in the normal mammary cells, it really didn’t work that well, it got degraded, it was really hard to maintain high levels of it. And so, the cancer cells may be arrested transiently, but it was not as effective. And so that’s what you want when you’re creating a cancer therapy, something that will have a lot of efficacy in a tumor cell and no efficacy in a non-tumor cell, right?

Joseph Kim:
You’re not just destroying every cell out there with chemotherapy and radiation, that sort of thing. And tell me about how were you dosing tissue and animals. Was it an injection, a liquid, a pill? How were those early dosing administrations?

Stacy Blain:
This is a peptide which is, a lot of our drugs that are on the clinic are what are called small molecules, and they’re like little tiny bits of chemistry. So they’re very small, they’re usually cell-permeable, they’re relatively easy to make and scale up. But we wanted to use this peptide, we didn’t say, like, at that time when we started, we were like, why wouldn’t we just do what nature does, right? Like, nature’s already figured this out. That’s like literally like a million years of high throughput screening … the best way to drug p27. So Alt being a peptide wouldn’t actually be taken up by the cell, so we had to find a delivery vehicle for it. So we used a liposome, and when we started, most people in the lay public didn’t know what liposomes are, but I think most people probably know what liposomes are now because of the COVID vaccine. And I call a liposome a lipid, a fat suitcase, essentially, that’s what it is. So we put this, the peptide, into this fat suitcase, and the suitcase would protect it because as it’s circulating in the blood of the animal, it would break down. But the fat suitcase is going to protect it, right? It’s like nothing to see here. You know, don’t break anything down, just floating around the blood, and the fat suitcase, fat likes fat, and our cells have a lot of fat on them, so it would sort of home to the tumor and then enable the peptide to sneak into the cell. And then, once the peptide was in the cell, it knew what to do. It went right to the nucleus, it found its targets, it inhibited p27, and it turned CDK 4, 6, and on. So that’s what we did. We put it into this liposome, and we could throw it on tissue culture cells, and it was taken up, and we could see look in varying like two hours, we can see it’s in the nucleus, great. And then we can inject it into animals, and we could see that, oh, look, it’s in the tumor. We can physically see it there, we could tag it and follow it with fluorescence, and then we also would see that when you shot it into the animal, the tumors disappeared, right? So that they could start it, they would start shrinking, and that could then extend the overall survival of these animals, whereas normally they had breast cancer and they were eventually going to succumb to their disease. Their tumors would get so big that they would die, and the tumors would shrink, and they would live five times longer than our untreated animals or even our animals treated with sort of the standard-of-care medicines in the clinic. So the drug today, we’ve done a lot of work. Those were our early sort of experiments. And so once we got to CONCARLO and really were focused on our vision to bring this transformative therapy to our drug-resistant patients, we had to change the peptide. The naturally occurring peptide protein was too big, so we made it much smaller. We bioengineered it to make a smaller form. We changed many of the amino acids to become different amino acids, so it would be more stable, that stability factor. And then we changed the lipid suitcase so that it was easier to manufacture, that it would avoid any kind of pitfalls, and we spent a lot of time doing that. And that was, as you know, again, back to the change in my mode, I was like, wait, we already have a drug, it works really well, why do we have to change it? Well, and then people would say, you need to change it because it’s got to be stable, it’s got to be manufacturable. You’ve got to be able to make the drug. It doesn’t matter that, …, you got to make kilograms if this thing works right. We got to make a lot of it. You’ve got to make it under GMB conditions, that means special equipment. And so we spent a lot of time doing that and brought in really amazing people. We’ve been really fortunate to be able to lure away people that had invested their entire careers in biotech and pharma and knew how to do all of these things. Dr. Krishna Alemany, who came from Bristol-Myers Squibb Turning Point, she had six drugs under her belt, 22 INDs, an IND is the approval from the FDA that you have to actually test it in humans. So she knew how to do all this work. And, you know, a lot of it continues, and you were continually refining. We just finished sort of our developmental CMC, and so that means like the manufacturing sort of like can we make it at scale? Yes, we can. And then we also learned like, look, we can’t make it ourselves. We’re a small biotech company. We’ve got to find clinical-grade manufacturers. And so our drug is made by Bachem Americas and … to world-caliber contract research organizations, and … makes a lot of COVID vaccine for Pfizer. And so that was part of the learning curve, which is like it’s not enough to just have a great molecule, because I think we had a really great molecule in the academic setting, it was doing lots of really interesting things. We needed to transition it into that consistent, scalable, stable, packageable transportable product, and that’s what we’ve done.

Joseph Kim:
So yeah, you’ve taken a very good drug as it was. You’ve skinned it down, you’ve taken it out of the giant suitcase, put it into a carry-on, right so more people can do it. You’ve hired.

Stacy Blain:
Great analogy.

Joseph Kim:
Yeah, world-class researchers who’ve got championship belts on her shelf and really great manufacturing facilities. But now it’s time to go into the humans soon, in the next year and a half or so, right? What scares you about going into humans and, not literally go into humans, but like scaling that research into humans because, you know, with a rat model mouse, larger animals, you can sort of do what you want. But with humans, it’s very complicated. Anything scare you about like scaling the human research? And then alternatively, does anything like get you excited and optimistic about doing that?

Stacy Blain:
I’d say it’s the same thing, right? So what scares me is that the reminder, which I say to myself every day, humans are not big mice. They’re not just big dogs or big rats, right? We are very complex species and lots and lots of drugs that have been brilliant in lower animal, you know, different animal species have not reached their endpoints in humans. So that is what scares me, is that we can be 100% right up until we dose those humans, and then unexpected things will happen. But the same thing, that same tenant also excites me because I think that we can use science to design those clinical trials to learn things. And so it’s, you know, not designing the trial to just say, did it work? Did the tumor regress or not, but design that trial to say we want to see, you know, what is the concentration of the drug in the blood? Is it high enough or long enough? Did it hit its target? Did it engage with the target? Did it bind to p27? Did it turn CDK 2 on? We need to design that trial to learn something. And that’s, again, back to my science lore, and that’s the sort of adages, the things that I always say to myself and say to my students, every experiment should teach you something, even if it is just, you know, like, oh, don’t do that. That’s not enough. Don’t do that because why? And so I think that is, you know, I’m excited about the power of science and treating this like we need to continue doing science even when we’re in those human patients. We need to learn things from that. And I think that is what really is getting me excited that we need to validate this target and show that we’re the only company driving p27, it’s never been a drug before, and so, we need to show that it has some efficacy and we can do it with low toxicity. And then that opens up the whole world for p27-targeting in the same way that we have many drugs that target the EGFR receptor, we should probably have many drugs that target p27, because there’s, lots p27 is involved in many, many tumor types, and there’s many different modalities. You know, I don’t know that the nanoparticle will work in the Liposome will work in every tumor type, many tumor types are very hard to deliver to, and so we need to come up with other approaches. And so, we do have different approaches to drug p27 in our pipeline. We have many different drugs that are not as far along as our lead. So we want to be successful in that clinical trial to prove the value of the target so that we can then target it even more. But I am a scientist, so I fall back on science and will continue to do really critical science, critical experiments, be highly critical of myself, critical of the research, critical of our team every step of the way. And I have faith that we’ll science our way out of any problem that we encounter, because that’s what we have to do.

Joseph Kim:
I love that answer. When you think about executing and designing the research, you’re not going to be just in an animal lab anymore where you can just put the rat back in the cage. People have their lives to deal with, and having, going through cancer treatment, whether it’s investigational or standard of care, is a harrowing experience. On top of that, you have the oncologists who you need to recruit these physicians to become investigators, and they have to execute the protocol with an exacting degree of excellence. How comfortable are you that you can design a study that can be executed with consistency and excellence and then provide a way to support a patient in their journey on research, which is in and of itself hard to do on top of a cancer treatment journey, which is, of course, life-threatening?

Stacy Blain:
Yes, that’s a great question, and I think that the way we addressed, it is, early on, in part from my academic background, we recruited three major, I’d say, really world-famous academic clinicians who run clinical trials at the Dana-Farber Cancer Institute, Columbia, and Memorial Sloan-Kettering Cancer Center, and so they have been on our scientific advisory board since our first year, and they have kept us true to the patient journey. When we originally started, we were dosing our animals really frequently, like multiple times 3 or 4 times a week, and they said, you know, look, someone who has metastatic breast cancer is not going to want to come into the clinic for a transfusion 3 to 4 times a week, that is not part of her or his journey. So you need to try to get that down to maybe one time a week, two times a week, and so that’s something that we have worked on and really thought about how these patients are. We’re dealing in the metastatic drug-resistant setting. We’re going to have ovarian cancer. Ovarian cancer is frequently diagnosed in the stage-three, stage-four setting. These are patients that are very ill and are very scared and, in many cases, unfortunately, have a terminal disease, and so we need to think about that. And we constantly remind my team about that, right? We have to create medicines that work with those patients’ lives. They are, frequently they have been heavily pretreated, which means they’ve been through five, six, seven rounds of prior therapy before we see them, so their cancers will be highly evolved, be very heterogeneous. We need to be thinking about that. And also very fragile, they cannot support and sustain and withstand a lot of toxicity. So that toxicity factor, in my opinion, is really, really important and is the cause of failure as many drugs, because a lot of drugs work, but if the patient can’t stay on it consistently or has to go off of it for a period of time, which many of the drugs in the oncology space we give them for 21 days on, and then they to let them patients recover, we take them off for seven days. That seven days is really an issue because their cancers are highly mutating and evolving, and by taking them off for seven days, we’re allowing, we’re almost pushing even more drug resistance. You know, the same way when your doctor says, you know, stay on that antibiotic for ten days, that’s because that bacteria is really rapidly proliferating, and if you give it the chance, it’s going to evolve away from the medicine that you’re taking. Cancer is exactly the same. So thinking about designing a drug that can intervene continuously, that can be given as infrequently as possible, that has as low as toxicity as possible. And then back to that beautiful space that we sit in, which is really surrounding ourselves with the most talented clinicians and chief medical officer and people that have done this before as effectively as possible, that’s where we sit right now, and I’m really excited to dig into that. You know, a huge problem in clinical trials is patient recruitment. Such a small percentage of eligible patients in this country join clinical trials, and then, if you go to a global perspective, we’re not running clinical trials as globally as we should because there are millions of patients out there that would benefit to be in these clinical trials and it would speed up the clinical trials, and that’s a way we could reduce the cost of the clinical trials and thus reduce the cost of the medicines we bring to clinic. So I think that thinking globally is something we’re really looking at. You know, should we be running our trial in collaboration with centers in Australia, which is a big place, in Europe, in India, in China. The goal is to recruit patients as fast as possible, run the trial as effectively as possible, learn as much as we can, and then get that that will help how we can get that drug faster. So really excited about this next part of the journey.

Joseph Kim:
Yeah, I love how you’ve come to focus on the patient because that’s where the rubber meets the road, and that’s where all the value is going to be seen. And if you can’t keep that patient in the study or the standard of care or their journey becomes too hard, even with an investigational medicine, you’re just never going to find your answer, and no matter how good the drug looks like in a rat, if it doesn’t play out in a human, the game is over. What can we do as an industry to help a prospective volunteer in oncology research specifically to better understand what they’re about to go through and really help them stay engaged, even when the chips are down, and things don’t look like they’re going perfectly well, which, you know, it’s cancer, it’s not going to go perfect. What are your thoughts?

Stacy Blain:
That’s a great point, and I hope that, I think that we are starting to leverage, you know, a lot of our technologies and those things that we carry around in our hands every day, those phones, apps, there’s a way to be really in constant contact with those patients, provide them access to talk to a clinician, a nurse practitioner, someone. This is what, I’m a patient, this is what I’m feeling. Is this normal? I’m scared. And so that again, thinking about toxicity, not just the physical toxicity that the patient is feeling, but, you know, financial toxicity, enabling them to stay at home and ask their questions so that they’re not incurring traveling expense and babysitting expense and loss of work expense. So I think that that’s one big change that is moving into clinical trials is using platforms, technologies, apps to help educate and sort of sit and stay with those patients in a really live time fashion. And look, we can do it to get a hamburger, you know, delivered to my door in 24 minutes. I think that we should be able to use these same apps and technologies to stay in contact with our patients, and I think that’s what’s really happening. And I think that would be a big, is a big transformative space so that the patients are not alone. A lot, you know, the beauty of a trial is that that individual patient is with a lot of other similar people, and so maybe there’s another 30 people or 100 people that are going through very similar things, and there’s always comfort as a human to talk to someone, talk to the people, not necessarily talk to the other patients, but talk to the clinician who can say, look, a lot of other patients are experiencing this. This is normal. Let’s monitor you. You know, I have many friends that have been in trials or have been on experimental medications. And, you know, having that constant contact or being able to get in touch with their clinicians or their nurses or the people running the trials, that’s really important, and I think that technology can help us. It’s a good thing that we’re in this technology-centric era right now.

Joseph Kim:
Yes. Doctor Blain, I love how we started the conversation, which is very scientific, and how we ended it, which is all about the humanities and like human behavior, and like you’ve really done an amazing job discovering this breakthrough molecule, creating a new class of drugs, let’s call it what it is like, and also not keeping the human side of research and medicine and science at the forefront as well. It’s really refreshing to see someone who’s got such a great 360 view of science and the science business. I really thank you for coming on the show today. I’m very excited about your next stage, and I wish you all the luck in your progress with CONCARLO.

Stacy Blain:
Well, thank you so much. It was a pleasure. And if any of your listeners want to learn more about CONCARLO, they should check out our website. You can find me on LinkedIn. As you can tell, I love to talk about science, and I love to talk about this journey. So thanks so much for having me.

Joseph Kim:
Thank you.

Joseph Kim:
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