B (3:40)

Well, it is a pleasure to be here as well, so thank you for hosting me and allowing me little time to tell our story. So histotripsy does feel like it came out of nowhere in a sort of this overnight success story, but it's been now almost 25 years in the making. What we do is incredibly complex and it's just taken us this long to get to this point. So we use non invasive, therapeutic focused ultrasound. So there's two types of ultrasound. There's the kind you use for diagnosing and looking into the body, and then there's therapeutic ultrasound. So just a much higher power and amplitude that you can deliver into the body to have a therapeutic effect. And 25 years ago, the researchers at the University of Michigan developed a way to use therapeutic focused ultrasound to liquefy targeted tissue. So you're delivering ultrasound energy from outside the body, inside the body, to a focal point, and we create pressures at that focal point that ultimately start to break down the tissue and the cells at a subcellular level. And it leaves behind a liquefication that then the body knows how to naturally process and remove from the body over time. So we're removing unwanted disease tissue from your body and doing that completely non invasive through histotripsy.

A (5:02)

And when you say that tissue, you mean cancer.

B (5:06)

So it is not specific to cancer. We are currently using it to treat tumors in the liver. We will be submitting our data to the FDA later this quarter, using it to treat kidney tumors. We will be later this summer delivering our data package to the FDA for the use of pancreatic tumors. So, yes, we have started our journey in cancer, but histotripsy can be used to treat any unwanted tissue in the body. So something like the prostate for men and a benign condition called BPH or in a woman, uterine fibroids, which often have some pretty massive symptoms associated with fibroids that, again, we think we can deliver the histotripsy effect completely non invasively to help those women or men, regardless of what they're dealing with.

A (5:56)

So it's currently FDA approved to treat liver cancer. Is it kind of last line? Is it first line? Are doctors sort of embracing this enough now so that if somebody is presenting with malignant tumors in the liver, this is a course of treatment that is.

B (6:12)

Offered to them the FDA regulates, based on our clinical data, where it can be used. So our first clinical trial was in liver tumors. And so we are indicated for the non invasive of liver tumors. And this can be any type of tumor. It can be primary liver cancer, patocellular carcinoma, or hcc. But the great majority of patients that we're treating, and you and I had talked about this, have cancer from another origin and now have tumors in their liver. So as an example, breast cancer. Unfortunately there are more women in the United States who have metastatic breast cancer and now have tumors in their liver than even patients with primary liver cancer or hcc. So a tremendous amount of women impacted by the tumors and ultimately those become fatal. And today they're almost completely unaddressed because there hasn't been a really good solution for those. So I think we're providing a wonderful alternative for women who want a better quality of life and want to potentially extend their life by getting histotripsy treatments. And because it's non invasive and because it's non toxic and usually with almost no side effects, they can get repeat treatments over time if they need them. The thing about liver tumors is that they almost always eventually recur. So the likelihood of having another tumor at some point is pretty high. And there's nothing that restricts a patient from having another histotripsy treatment down the road. The same is true for primary pancreatic cancer patients. Many of them end up having tumors in their liver which become fatal. It's how my dad died of primary pancreatic cancer. But it ultimately was his liver tumors that became fatal. And we provide an alternative for those patients. So our first FDA indication is for the destruction of liver tumors. And then we'll be submitting our data, as I mentioned, on kidney and then pancreas. We've begun a trial outside the US treating benign prostate disease, as I'd mentioned just a little while ago. And the plan ultimately over a period of time, is to be using histotripsy throughout the body. We've got a very active brain program as one example. We are in the process of working through how we move that from research into the clinic and start human trials. But this could be used for neurological disorders, things like epilepsy and Parkinson's, both benign and malignant, and even in blood clots. Anything that we can target and liquefy and have a therapeutic effect is a potential clinical application.

A (8:47)

The current treatment for liver cancer involves radiation for small tumors, chemotherapy in certain instances, surgery. Could you go to histotripsy first or is it considered sort of more experimental at this point?

B (9:04)

So the FDA regulates what the treatment is indicated for, so starting in liver tumors, but it does not regulate how a physician uses a therapy. So it's to the physician's discretion, consulting with the patient as to whether they want to get a histotripsy procedure or not. So for patients with liver cancer or liver tumors, generally the gold standard is surgery. If you can have a surgical resection or a transplant, those are considered the gold standard options. Unfortunately, 80% of patients who have liver cancer or have tumors in their liver are non surgical candidates. There are a variety of other options. As you had mentioned, there's radiation, you can use heat to burn the tumors. It's really the decision that's made by the physician and the patient. I would say the majority of patients we're treating today are more advanced stage patients who either do not qualify for those other procedures or have had those other procedures and now they're recurring again. And they choose histotripsy as sort of their last option. But there's nothing to preclude a patient and or a physician coming to the decision that they'd like to use it as a frontline therapy. That's completely their medical judgment. I get the question a lot. Why haven't I heard of this? If it's this revolutionary, you know, why hasn't been on the news, why am I not hearing about this? I think it's largely because medical devices are regulated very differently than pharmaceuticals. And so if you've got a breakthrough drug, it goes through incredibly rigorous clinical trials, phase 1, 2 and 3. And by the time you get through the phase 3 trial, it's really big news. Especially if it meets a significant unmet clinical need. It's going to hit the nightly news. You hear about it, so there's a lot of media attention. Medical devices are just a little bit different in terms of how they're regulated. Some of the branches within the FDA just consider them a tool. And so we are a tool to destroy liver tumors. And for that reason, they're a little bit more lenient in terms of the data that's required to get clearance and to allow a physician to begin to use it. So over time we will build the clinical evidence similar to a pharmaceutical that gets all those headlines and splash, but that's generally not needed in order to get a medical device cleared. And so I think that's why it's not on the nightly news yet.

A (11:35)

I think I would really love to understand what the outcomes are that you have seen. We talked a little about this when we first met, but I would love to hear some of the real life stories of what you've seen using this technology.

B (11:50)

What makes it incredibly unique is its safety profile. Because it's non invasive, we don't enter the body with anything other than energy, it's non toxic. So it's very different than radiation therapy. And generally speaking, depending on where you're treating in the liver, there are usually almost no side effects. And so it's this massive paradigm shift in the world of treating tumors where everything prior to histotripsy, which was cleared about two years ago, was either invasive, toxic, or generally comes with some pretty significant trade offs in terms of side effects. And histotripsy is none of those, which I like to say is just more forgiving than any of those therapies. It allows physicians to apply in a broader number of use cases, just different types of scenarios where a physician says because it's non invasive, non toxic and almost no side effects, I can use this here where I wouldn't use something else.

A (12:52)

Meaning like treating very early stage or.

B (12:55)

Even very late stage. So generally a patient becomes very advanced, they've got lots of tumors. The reason that a physician will tell a patient there's just nothing left we can do is because of the trade off of doing something invasive, toxic or with side effects. So even changing a drug at some point, the toxicity of those drugs can be so severe that it's just not worth doing that. And it's just live your life as most comfortably as you can for whatever time you have. And honestly, a majority of our patients, patients are self referred. They're finding about histotripsy on a Facebook page, they're reading about patients who are very similar to them or people with very similar conditions who have been told they don't have options left. And they're finding patients who have found histotripsy and it's improved their life, starting with their quality of life. And sometimes they almost have to convince their physician to try it. But their reality is they've been told, many of them, that there's no options for you left. And now There is an option for a lot of these patients because of its safety profile, because you're not going to invade the body, you're not delivering something that's toxic. And generally, these patients have nothing to lose. And the mechanism of action, as I mentioned early, we're reducing pressures in the tissue in the tumor. The liquefaction process of the tissue and the tumors reduces pressures. Those pressures are oftentimes what causes the patient a lot of pain. So a lot of these patients, you know, someone with advanced stage cancer, especially if it's metastasized their liver, they tend to be in a lot of pain and discomfort from the size of the tumors, from the pressure that the tumor is putting on the capsule of the liver or something else. And through the process of histotripsy and liquefying the tumors in the tissue, you can rapidly and immediately reduce those pressures, which can provide some pretty dramatic symptomatic relief. And as a company, we think that's a wonderful place to start. And if that's all we ever did was put a patient who doesn't have a lot of options in a better place in terms of their quality of life. I know my dad would have wanted that for whether it was three months or six months that he had to live. He was in such awful pain from his liver tumors and his pancreatic cancer. If we could have just made his life better for whatever time, time he had, he would have signed up for that every day of the week. And so we start with the biggest group of patients who have liver cancer or tumors in their liver are the more advanced stage patients, because there are so few options for them. And if we can, from a palliation standpoint, just put them in a better place physically, it's just a wonderful place for our technology to begin. You can then build the argument to, well, then why wouldn't you use that as frontline therapy? There's nothing to preclude you from having a future surgery or having radiation. We would always recommend, if the patient is a candidate for chemotherapy, that you do both histotripsy and chemotherapy, because most of these cancers are systemic disease. It's in your blood. And so you really do want to use systemic therapies to help combat the cancer as well. But you can build the argument, and patients are building the argument, why wouldn't I start with a histotripsy procedure? And if that works, there's nothing else I need to do in the future. And if it doesn't work, I can either have another histotripsy or I can have some other procedure if I think that's needed. So if you were to go to our website and look at patient testimonials, you will find it is libraries of patients who have been told there really are no options for them. These tend to be young patients, which is really sad. And they're patients who have kids and they desperately want to continue to live, to be a mother or a father or see whatever the next event is. And they have found histotripsy and they've reasoned with themselves and the physicians. No reason they wouldn't try this. And you'll hear one patient tell you that the tumor board, who makes these decisions has said histotripsy is really the only thing she has left. Her name is Joy, and she's an oncology nurse. And that's okay because I've had now multiple treatments and I'm doing great. And as long as I have something and histotripsy, that's something. And I think the reason for that is why the majority of our patients are much more advanced stage. If there's nothing left, why wouldn't you try versus it's a lot harder to convince a physician to use something that doesn't quite have the clinical data yet to supersede something that's probably got many, many years of robust clinical data. We're in the process of building that clinical data.

A (17:32)

We're also living in a time where many patients are thinking about their health very proactively and doing things like advanced mri, full body screenings annually, et cetera, and being diagnosed with things very, very early. Sometimes when cancers are at 1 millimeter and still encapsulated. So does this come at a good time in terms of early detection? Like, is this still something that physicians, you think would not use as the first line, Even if it's very, very tiny?

B (18:05)

We think that's a wonderful place for histotripsy to exist. And there are millions of patients who are walking around who have an indeterminate nodule. It's something we saw. You know, you can hurt yourself playing tennis, go into an er, have an X ray or a CT scan, and they find something that they weren't expecting, but that something may not be big enough, and they want to watch it, and they want to see how fast it grows or does it grow. And I think there will be a reality where someday you'll just histotripsy it. Why would you be on active surveillance or watch and wait? Again, it's so paradigm shifting that you've got something that Is non invasive, non toxic with almost no side effects, but benign malignant. Why would you risk it? Why wouldn't you just treat it and be done with it and not have to worry about it again? So we see that as an enormous opportunity of where the technology will reside in the future. And we also see those diagnostic scans as someday being standard of care. The dilemma is who's going to pay for all of those scans? It usually comes down to cost and money and who's going to pay for it.

A (19:10)

But presumably if we're able to diagnose cancer very early and there's an ultrasound solution, I mean surely over time, like it's more expensive for the insurance companies to be paying for surgery and chemotherapy.

B (19:24)

Et cetera, the expense of invasive surgeries and other procedures is astronomical. And so if we could figure out a cost, I can't think of a justification why you wouldn't have every patient have an annual CT Mr. Where you're detecting nodules, you can treat them non invasively. You would eliminate theoretically all of the costs of the downstream procedures once that patient is determined to have cancer or some other disease, for sure.

A (19:56)

I've always loved sitting with a question a little longer than necessary, following threads, getting curious about why something works. Flawed is an AI I've started using for that kind of thinking. It doesn't just get give you an answer. It asks follow up questions, challenges, assumptions, treats the topic like it's worth exploring. And it's built to be balanced, not to feed you whatever keeps you engaged. If you're someone who loves going down thoughtful rabbit holes, try Claude for free at Claude AI Goop. I know that it's only cleared currently for liver tumors, but what are the other cancers that you feel there's a good chance that this could be efficacious for? And are there any that you don't feel like based on placement of the body, behind bones or like in the blood, harder to pinpoint that aren't a.

B (20:57)

Physical tumor, Blood definitely becomes a little bit more challenging because it's not a target. I think that's an easy way to think of it. We'd like to have something that we can physically target again. It doesn't have to be a tumor. It could be kidney stone or a gallbladder stone, it could be a blood clot. But something that we target the blood is a little bit more challenging. I made the comment early on that it's taken 25 years for us to get to this point. The really complex R and D work is behind us. It's taken that long to get to where we are. And we really believe that technically, now and procedurally, there's almost nowhere in the body that we can't treat in terms of organs. The lungs create the most complexity because of the airways. Air is a blocker of ultrasound because of the complexity of the airways. The lung becomes more challenging. But outside there's procedural ways that we can overcome that. But it's the most influx beyond that from anywhere in the brain, non invasively, throughout the head and neck, throughout the body. We don't believe that there's anywhere we can't technically and procedurally deliver histotripsy. And so we've got projects that we're starting with the most recent use of proceeds, most recent financing where we'll be accelerating work in thyroid tumors, breast tumors, bladder cancer, I mentioned uterine fibroids, spine tumors and anything in the brain. So we believe that all of those are very realistic future applications. And then beyond that, we can deliver histotripsy to overactive nerves that could be one of the factors to hypertension or high blood pressure, as one example. So the clinical implications long term for delivering non invasive energy with a therapeutic effect almost anywhere in the body is pretty profound.

A (22:50)

Is it painful?

B (22:51)

Most of the patients experience no discomfort or pain. Some of the patients, depending on how we position them. So the patients are positioned to optimize the beam path into the body, into the target. And if they're positioned in a weird way and they're an older patient, they're not used to being on their side for an hour and or we're treating through heavy blockage like the ribs, they can experience some pain that many would describe as feels like they did too many sit ups the day prior and they're feeling achiness. But generally within 24 to 36 hours that's gone right.

A (23:27)

And compared to the long tail impact of chemotherapy, surgery, healing, it's very minimal.

B (23:34)

And for the patients again that are having histotripsy for palliation, they've got really severe abdominal pain. It is immediate. It is generally a drive home from the hospital and they're texting their physician that they haven't felt this good in months or whatever it is. The only other technology or modality that's really used for that is external beam radiation. And a radiation oncologist will tell you sometimes it's actually worse for several weeks before it gets better, even if it does get better. And then there's other side effects to all of that. So I think it's one of the most amazing things is it's immediate and virtually without any side effects.

A (24:12)

I lived through the side effects of radiation with my dad's throat cancer, and it was just gruesome. I mean, just awful. Just absolutely awful. And his treatment overall was so extreme and so. I mean, invasive isn't even the word. Like, we had days where we thought, you know, is this worth it? The whole inside of his throat was burned from the radiation. He couldn't swallow. I mean, it was barbaric.

B (24:34)

You know, really, I believe that there will be a day when we look back and say, I just can't believe we did those types of surgeries. I can't believe we used radiation in that location. The side effects are just so extreme. I really believe that we can eliminate a lot of that.

A (24:53)

So what does it feel like for you to be sort of spearheading that? I mean, I think any one of us who's witnessed someone that we love go through cancer treatment as it exists today, I think we've all had that conversation, right? I can't believe that this is the way that we address this disease. What does it feel like for you to be spearheading this technology and this modality?

B (25:16)

On one hand, it is the most gratifying. I don't even want to call it a job position that I could ever have. I never would have dreamt that I'd be the CEO of a company that's doing what we're doing. And I just excited to go to work every day and motivated to go to work every day. It is unbelievable. And the patient stories it is daily. And you would ask me about the patients. I mean, just changing the trajectory of one's life. People who are told that they're terminal and they have a limited number of days left, and then they just have hope. They drive to the hospital with hope that histotripsy is going to change their life and improve their life and hopefully extend their life. The only thing I can equate it to is raising your kids and the gratification of watching them grow and develop and become young men and women and succeed. Like, it's the only thing that I can compare it to. In addition to that, though we talk about this as a company, we feel like we have incredible responsibility. I do believe that this is so profound, and we just need time to get the clinical data published that'll move physicians and will move guidelines, but we just need time to develop the evidence and have that published. But we have a responsibility to provide this throughout the world so that Patients have access to it for whatever their need is. And we've got a responsibility to build the data throughout the different organs. Because whether it's breast cancer or bladder cancer or brain cancer, the number of inquiries we get every day of a patient who has one of those cancer types that we're unfortunately not allowed to treat today, it's just far too many. So it is also we talk about the responsibility we have as a company to go as fast as possible. The challenge is faster we go without the clinical data that many physicians need, you know, the more criticism we take. But that's okay. We see firsthand the patients that we're helping.

A (27:13)

And you do have clinical data for the liver. And then what, from a roadmap perspective, are these clinical trials happening in parallel or are they in a certain order? And how long do you think that the process will take? I mean, what are the rules around an off label use for something like this? Just to try it.

B (27:32)

Yeah. So in going back to the data. So if there is a criticism, it's that we don't have the clinical data that a drug would require to do the same thing. Because the FDA regulates them very different, differently. So if you were going to launch a drug to treat liver tumors, the FDA would require you do three types of different studies, starting in safety, but ending with efficacy. Doing a randomized controlled trial, looking at five year survival rates. I don't know if we'd have a company right now, if we had to go through as a medical device company, the same rigor. So the data that we have is short term and really it addressed safety and then short term efficacy. So the critics would say, well, this just isn't in cancer, what we consider standard data. We want randomized controlled studies, 5 years. The patients are saying though, but why? Again, most of them are so advanced that why do I need all of that data? Why wouldn't I try this if it's safe? The FDA has said it's safe, it's got short term efficacy and it's non invasive, non toxic. Why wouldn't I try? So we do have data. But to be fair, the critics would say it's not the level of evidence that a drug would have to get a similar indication. But that's not really the company's decision. It's how we work with the agency based on the fact that we're a medical device and they're just regulated very differently. We do now have data that we've collected. It's very similar to liver. It's more short term Acute safety data, but we have it for liver tumors that we'll be sending for our kidney tumor indication this year and the same for pancreatic tumors. And then it's the same process. We'll do the same for all the different tumor types or different diseases that we want to treat. And so the process is we work with the FDA on what those studies look like, we determine how many patients are needed, what the endpoints are, we do the studies, we submit them to the FDA and hopefully get the indication. The technology and has been designed and built to do all of it. We wanted to do the heavy R and D work up front, not have to modify the system for each new indication or application. So the Edison platform, which is the robotic system that delivers histotripsy, has been designed to treat everything from the head and neck down through the body. The neurosystem is a different system with the transcranial cap that goes around the skull. But everything else can be done with the Edison system as it is designed. Which then means you had asked about off label use, that there's nothing really to prevent a physician and a patient making a medical decision that they've got a tumor somewhere in their body that can't be treated with other modalities, but could be treated with histotripsy. If they decide that it's medically reasonable to use histotripsy off label, they can do that. You had asked about patient stories. We've got wonderful. I mean, it's not wonderful in that unfortunately for this 34 year old woman, she's got a very aggressive type of sarcoma that creates spontaneous tumors throughout her body. And so it started with some tumors in her liver. She discovered histotripsy, had histotripsy procedures. Those went very well.

A (30:46)

Sorry. And when you say they went very well, they become undetectable.

B (30:50)

Yeah. So you treat them, you destroy them. And then through imaging, Whether it's a CT Mr. Or PET scan, they are confirmed to be dead. So, yeah, that's what we mean when that's successful. And then she had one in her thigh. Well, she's a runner. That created an awful lot of discomfort, could no longer run. And she was the first to ask, can I have this of the big large tumor on my leg? And so the physician said, technically and procedurally we can do that, but it's never been done before, so you're gonna be the first. And what are her alternatives? And so she was treated again very successfully and sent pictures the next day of her thigh, which looked great. And she went for a run and she said she hadn't felt that good in quite some time. And then a month later ran her fastest marathon that she had ever run. And then she had another tumor appear up on her shoulder and she had a histotripsy of that. So the unfortunate part of that is that insurance isn't going to pay for off label utilization. So the hospital negotiates with the patient on what that would cost. But for a patient like that, the alternative isn't good if these tumors are going to go untreated. And so I think she's now had either five or six histotripsies throughout her body. And the last I heard is doing fantastic. So again, back to your question around these diagnostic scans. I look at a patient like that and say, this is the future, hopefully we catch it really early. A6 exist before it's become a cancer, whatever it may be. Indeterminate nodules. You just treat them before they become anything. And you treat them before you have to worry about them becoming everything. And some of these patients are becoming sort of poster childs for the reality of that. We've got another patient who is now the first in the world who has had their liver tumors treated, their primary pancreatic tumor treated, and they had a tumor in their kidney treated as well. So you can imagine a day where if it comes back, whenever it comes back, wherever it comes back, you can have a histotripsy treatment and go back home and go back to your normal quality of life.

A (32:49)

That's amazing. I mean, especially for these cancers that are largely incurable or incurable like glioblastoma, pancreatic cancer. Obviously ovarian cancer is very hard to treat. Like why wouldn't at the onset. I've just witnessed people that I love go through these particular things and I just, I wonder why there would be reticence to adopt something like this very early. I understand the late stage adoption, but you know, in something like glio or pancreatic, why a doctor wouldn't try this first?

B (33:21)

Medical oncologist or oncologists who manage these patients, they are very data driven. And you have a responsibility as a company to develop the data that will compel the oncology community. Right now we've got enough to compel patients. We don't have enough to compel the medical oncology community. And for every one of these new indications like glioblastoma, a really important one for us, some of them require a massive amount of data. We just need time to build it. But another Important part of the story I think you and I touched on when we first spoke. We haven't touched on it here, though, yet. So knowing that we were going to start in cancer, we started in very aggressive melanoma models and then began doing liver cancer models, pancreatic models. You mentioned glioblastoma. That's what triggered this thought. We're doing glioblastoma models today. And 10 years ago, the question was, if you're liquefying cancerous tumors, could you be spreading cancer? If that liquefaction gets absorbed by the body, which we know it does, could cancer cells be transported through this process of being absorbed by the body and spread cancer? And immediately in these experiments, we learned that was not the case. The arms that did not get a histotripsy procedure, they just get the tumor, they die pretty quickly. But in the arm that got histotripsy treatments, they survive. What we learned through those experiments over time is that even when we only partially treated a tumor with histotripsy, at 30 days, the tumor was completely necrosed or dead, even when we left tumor behind to create sort of a worst case scenario to see if we could get the cancer cells to be transported throughout the body. So, so then we would implant multiple tumors, partially treat one tumor, and at 60 days, we'd see both tumors completely die, Almost like we were delivering a systemic drug therapy. So what we've learned is that histotripsy creates programmed immunogenic cell death. So what happens is that this liquefaction has antigens in it, proteins from the membranes of the cells that does get transported, and it can awaken the immune system.

A (35:27)

Right, because part of the issue with cancer is that the immune system is not recognizing it quickly enough. Right?

B (35:33)

So cancer's so sly and it goes undetected. It knows how to hide itself from the immune system of the body, which is why in lung cancer, pancreatic cancer, they're diagnosed so late. Because until you have symptoms, your body doesn't recognize that it has cancer. By the time you have symptoms, it's generally too advanced and too late. So. So when we liquefy these tumors, we release these antigens that can awaken the immune system, and then the immune system starts to attack it like it would any common cold or the flu or anything else that your body has. Now it knows it has cancer. So we do believe that this will be a significant part of our capabilities. So you had asked about patient testimonials. Again, if you go to our website and look up the Patient testimonials. You'll meet a woman named Emma. Emma, who traveled from Wales, I believe, to the US to be treated. She was told she's terminal. She has young kids. That's not acceptable. And she found a center in the US who would treat her. And in the video, she says she has 22 tumors in her liver. And she had three treated. And over the course of three months, ultimately, they were all necrosed and dead. And so she went from terminal. And she explains it in the video that she went from processing. I have six months to live. And how do I tell my young kids, you think about how that hits a patient when they hear it? I watched this video. I've watched it, I swear, a hundred times. And it hits me the same every time when she's processing. I've got to go tell my kids. I just can't even get my mind around, like, having to tell your kids that you have six months to live. So that wasn't acceptable. She went to a Facebook page and read about histotripsy and women in her same situation. And she still alive today and doing incredibly well, and to my knowledge, still has no more tumors in her liver. And I think you could argue that this patient had an immune response that was pretty spectacular, that just by treating the three tumors, she had a response in the additional 19 of her tumors. And so that definitely does not happen in every patient, but it does happen in a certain number of patients. So now, as a company, we want to understand how we really optimize that. We have incredible control of many different parameters of how we do, but we do deliver a dose to each patient, and that dose can be modified over time. And so it's possible that if we change the dose, we can optimize this immune response and then, you know, hopefully also learn more about how we can work synergistically with the breakthroughs that are happening in immunotherapy, because mechanistically, they do work differently. And if we can use an immunotherapy to unmask these tumors and antigens that we release in situ to create a flood of lymphocyte activity and positive immune system activation in the tumor, it could be a really powerful combination, whether it's early stage disease or more advanced stage disease. But there is a whole other element to what we do beyond just liquefying and destroying. There's also this element of antigen release that we think could be a significant part of the cancer story long term.

A (38:41)

If somebody has, like you said, somebody had metastatic breast cancer as the primary site and then it metastasized to the liver. And you're able to treat the liver. If the body is able to have this immune response to the remaining cancer, does it go to the primary site of the initial cancer and do the same thing there? I mean, is that the hypothesis that you can treat it backwards?

B (39:08)

Absolutely. The long term potential, we now have a couple of spectacular case reports. There's too few of them. Again, we need to work on how we optimize that. But you're absolutely right. So if it's the same cancer type. So we have a patient, it's been published, where the patient had liposarcoma and it originated in the pelvis. They had a large pelvic mass causing a tremendous amount of discomfort. It metastasized to the liver. So now you've got the same pathology, the same type of cancer, both in a pelvic mass that was 12 centimeters in size, large, and then you've got tumors in their liver. And the patient went through multiple sessions treating their liver tumors and had a reduction in the pelvic mass by over 50%. So by treating the liver tumors, you ultimately had a response in the pelvic glands. We had another example of that in the pancreas and one in the lung.

A (40:05)

From the liver or the pancreas?

B (40:06)

No. So from treating the liver and had the response in the primary lung tumors, or treating the liver and had a response in the primary pancreatic. So again, how do we optimize that and change it from just a couple of case reports to the majority of patients who need that? But what's important to know is that we really believe we've got the ability to modulate the dose to over time create that optimization. Again, it just comes down to needing the time to do the studies to understand what dose for each pathology. But the potential is absolutely there.

A (40:39)

I think. I read that you've raised quite a bit of capital at this point, right? So I assume you're well capitalized to run all these trials. I mean, it seems like time is of the essence with this.

B (40:50)

It all ties together the economics and the financings to what a company can do. And we were a young starving early stage startup for a very long period of time. And so you can only do so much work when sort of living hand to mouth being funded and funding your projects. We incredibly fortunate that over the last couple of years have raised close to 500 million in capital, which is significant for a company like ours.

A (41:19)

And what happened? What was the inflection point there. Did you have, like, a particular breakthrough with the technology or why were you able to go out and raise that amount of capital?

B (41:28)

So what we do is so challenging, it defies conventional ultrasound engineering wisdom. And I think there was a large population of people who knew what we were doing, who thought we'd never succeed and never get our first FDA indication. Just too complex, too difficult for the FDA to understand, or just not successful doing our procedures. So In October of 2023, when we got that indication, our first FDA approval or clearance and delivery indication, there was an incredible amount of awareness that was created. And then the next question is, will anyone want it? Will anyone buy it? It's one thing to get your FDA clearance, but a lot of companies die after that if they don't have customers who want it. I would say the demand of histotripsy in the Edison system, I think, is one of the most successful stories in the history of medical device. And the demand was incredible. Within an hour of announcing that we had FDA clearance, the Cleveland Clinic placed our first order, and we had 20 within the first couple of months and began installing systems. And that confidence with investors that there was going to be a demand for this product. We had demand internationally. We began shipping systems in geographies like Hong Kong and Singapore. That led to the confidence that this was not only a real therapy, but it was going to be a real business. And so it was all about investor confidence, confidence in the team, confidence in the technology, confidence that we've built something that would be of high demand for patients, for physicians, for hospitals. And so it just led to a series of multiple financings within the last two years, which now affords us to be able to fast and accelerate projects through all these different potential clinical applications throughout the body.

A (43:14)

Yeah, obviously, I mean, when you're looking at diseases like cancer that are fatal, I can obviously understand why that's the priority. But I think, you know, when you talk about benign tumors or fibroids, what I'm thinking about through the lens of women's health and how many women struggle with polycystic ovaries and fibroids. I mean, you mentioned fibroids, but is this something that could address PCOs, all.

B (43:38)

Of it, procedurally and technically, there's nothing that we can't do and. Or can't overcome. If there is a limitation in today's system, like fibroids, is an example of one where the current system configuration can just treat fibroids. And so this year, we will be in the clinic treating women with fibroids, it's possible we learn something about that particular condition or disease that we need to modify something. But there's so many different parameters that we can modify that really the considerations become regulatory and clinical. How much is the FDA really going to challenge us or work with us more collaboratively? And it's because the FDA has so many different branches that manage these different areas of the body. Some are more conservative than others and those are considerations that we need to make. That said, being well financed does change the equation a bit. There's just more that we can do. I have a neighbor, unfortunately, young female, three young kids, my kid's age, and she just passed of metastatic breast cancer. And it was in her spine, it was ultimately in her brain. And the other neighbors are asking my wife why can't she have histotripsy? And the brain lesions we couldn't have treated today. The other lesions we could have, but it would have been off label and just such a sad story. And it's so common. I mean it's just far too common. And there's probably oncologists listening to this when it airs that are rolling their eyes. But I promise there will be a day where we can treat all of those tumors, whether they're in the brain, starting with the breast, and if it's primary and it's early, we can treat that. You won't have to go through radiation. My sister in law has been through primary breast cancer and had the surgeries, and had the radiation and had the chemotherapy. The wonderful news is that 95% of women, the five year survival is wonderful, but the means to get there is miserable. And histotripsy can help with that. And so whether it's early stage primary breast cancer, it's one of the easiest targets in the body for us to treat. We just need to do the clinical trials. But for the patients who unfortunately do recur and ultimately have tumors throughout their body, spine and brain, two of the more common, but liver as well, there will be a day where histotripsy will be there to treat all of those. And I'm just totally convinced of that. Technically and procedurally we know we can do it. We just need the time to get the FDA clearances.

A (46:00)

And what is the time frame?

B (46:01)

It's different for each one of them. Some of them will be really fast, some of them will be really hard and arduous. And we would have never done three to five years ago as sort of a starving early stage startup company. But now that we're Funded as well as we are. There's really nothing we can't start to take on either. It's really just becomes negotiations with the FDA in terms of what they're going to require in terms of data.

A (46:26)

There really is like a whole economy around traditional cancer treatment. The drugs, for one, the surgery, the radiation. I mean, someone very close to me underwent proton radiation, and I was astonished. It was $300,000 to treat, but there's a systemic treatment complex in place for cancer. I mean, am I being cynical? Do you worry at all that this treatment, which is far less expensive and would kind of undo some of that revenue, do you worry at all about being opposed from those behemoth industries that don't want to see something like this?

B (47:01)

I don't think so. I totally get that question. I get why people would be cynical. I don't think so. I think a lot of our users who are adopting are surgeons. Many of them would tell you, yes, they can see a day where this replaces a lot of open surgery or even minimally invasive surgery, but that's not a bad thing. And we've built the system so that they can use it. They can replace their surgical procedures with histotripsy, and they can do them and benefit from that. I think we'll look back and there will be a day where we cannot believe that we used to do invasive surgical procedures. That said, that's not the world we live in today. And surgery is considered the gold standard. And if you talk to our users, they'll tell you they're actually doing more surgeries today because they are using histotripsy in a way that can treat a tumor that they can't get to surgically or with radiation. And they take a patient who's not a surgical candidate to one who is. And I would argue that I would just want more histotripsy. But their mindset is this is the only way to really, truly have a potential chance at a cure. So we're going to do the histotripsy, and then we're going to do the surgery. But most of those centers are doing more surgeries. I think you and I would probably want to see less surgeries happening over time, but I think that that paradigm shift will happen, too. But I don't think we're a threat to surgeons or interventionalists who do other procedures. I think maybe some they really didn't understand our story would think that the pharmaceutical companies would be threatened, but we don't believe that at all. There's always going to Be a place. It's cancer, it's systemic. You want to get cell that's circulating throughout the body. Systemic therapies have a real purpose. I know they have real side effects too, but they have a real purpose. And we really believe histotripsy works very synergistically. Not only synergistically for other procedures like surgeries. Patients have to discontinue their systemic therapies, at least for a period of time that's not optimal for a patient with cancer. You can continue patients on system systemic therapies with histotripsy. It's very unique that way. So I actually think that from that standpoint, pharmaceutical companies should welcome and patients should welcome histotripsy as an option. So I understand why people would ask that and why people would be cynical, but I don't think so.

A (49:14)

Last question. If there's anybody out there listening to this who is suffering from cancer personally or has somebody that they love who's suffering, I think we all do and they want to learn more about this or understand where they could get this done. You mentioned Cleveland Clinic. What resources are there?

B (49:31)

If you go to our website, histosonics.com histo, which means tissue in Greek, sonics histosonics.com there's a physician finder on our website and they can find locations there. They can also email the company. We're happy to help triage. We do it every day. Patients who come directly into our histosonics email, but the physician locator is probably the easiest way.

A (50:00)

This is so exciting and I feel so hopeful listening to you talk about this. In terms of where we're headed, it's just utterly wonderful.

B (50:10)

The audience. If you have 5, 10, 15 minutes, go to the website for find the patient testimonials and just start watching. It is unbelievably moving. We don't sell these patients what to say. It's all in their own words and there's never a dry eye. It's just unbelievably compelling and gives me such hope for the future and where this is all headed. So thank you, Gwyneth, for taking the time to listen to the story and promote the story. We're going to be doing amazing things in this world.

A (50:43)

So awesome. Thank you so, so much.

B (50:45)

Yes. I hope we get to talk again.

A (50:52)

Thanks for tuning in. This has been a presentation of Cadence 13 Studios. I hope you'll listen, follow, rate and review all of our episodes, which are available for free on Apple Podcasts, Spotify, Odyssey or wherever you get your podcasts.